Tofacitinib

12.1 Mechanism of Action Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC 50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

1 INDICATIONS AND USAGE XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) are Janus kinase (JAK) inhibitors. XELJANZ tablets and XELJANZ XR are indicated for the treatment of adult patients with: • Moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF blockers. • Active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. • Active ankylosing spondylitis (AS), who have had an inadequate response or intolerance to one or more TNF blockers. • Moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers. XELJANZ (tablets and oral solution) are indicated for the treatment of pediatric patients 2 years of age and older with: • Active PsA, who have had an inadequate response or intolerance to one or more TNF blockers. • Active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use : • Use of XELJANZ/XELJANZ XR for RA, AS, PsA, or pcJIA in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.1 , 1.2 , 1.3 , 1.4 ) • Use of XELJANZ tablets and XELJANZ XR for UC in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.5 ) 1.1 Rheumatoid Arthritis XELJANZ tablets and XELJANZ XR (extended-release tablets) are indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of XELJANZ tablets or XELJANZ XR in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is n

2 DOSAGE AND ADMINISTRATION Recommended Evaluations and Immunization Prior to Treatment Initiation • Prior to initiating XELJANZ/XELJANZ XR, consider performing an active and latent TB evaluation, viral hepatitis screening, a complete blood count, and updating immunizations. Avoid XELJANZ or XELJANZ XR initiation if absolute lymphocyte count <500 cells/mm 3 , an absolute neutrophil count (ANC) <1000 cells/mm 3 or hemoglobin <9 g/dL. ( 2.1 ) Important Administration Instructions • XELJANZ XR (extended-release tablets) is not substitutable with XELJANZ (tablets and oral solution). ( 2.2) • Switching between XELJANZ and XELJANZ XR should be made by the healthcare provider. ( 2.2 ) Recommended Dosage Adult Patients with RA, PsA or AS • XELJANZ tablets 5 mg twice daily or XELJANZ XR (extended-release tablets) 11 mg once daily. ( 2.3 ) Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Who Weigh At Least 10 kg • XELJANZ (tablets or oral solution) 5 mg twice daily for those ≥40 kg or weight-based equivalent twice daily for those <40 kg. ( 2.4 ) Adult Patients with UC • Induction: XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily for a maximum of 16 weeks. Discontinue XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. ( 2.5 ) • Maintenance: XELJANZ tablets 5 mg twice daily or XELJANZ XR 11 mg once daily. For patients with loss of response during maintenance treatment, XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response. ( 2.5 ) Dosage in Patients with Renal Impairment or Hepatic Impairment • Use of XELJANZ (tablets and oral solution) or XELJANZ XR in patients with severe HI is not recommended. ( 2.3 , 2.4 , 2.5 , 8.7 ) • See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI. ( 2.3 , 2.4 , 2.5 , 8.6 , 8.7 ) Dosage Modification See the full prescribing information for dosage modification by indication for patients who concomitantly use CYP2C19 and/or CYP3A4 inhibitors and patients with lymphopenia, neutropenia, or anemia. ( 2.3 , 2.4 , 2.5 , 7 ) 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating XELJANZ (tablets and oral solution) or XELJANZ XR (extended-release tablets), consider performing the following: • Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to XELJANZ/XELJANZ XR treatment [see Warnings and Precautions (5.1) ] . • Viral hepatitis screening in accordance with clinical guidelines [see Warnings and Precautions (5.1) ] . • A complete blood count: Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a lymphocyte count less than 500 cells/mm 3 , absolute neutrophil count less than 1000 cells/mm 3 , or hemoglobin level less than 9 g/dL [see Warnings and Precautions (5.8) ] . • Baseline hepatic function evaluation: XELJANZ/XELJANZ XR is not recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . • Update immunizations according to current immunization guidelines. The interval between live vaccinations and initiation of XELJANZ/XELJANZ XR should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Warnings and Precautions (5.9) ] . 2.2 Important Administration Instructions • XELJANZ XR (extended-release tablets) is not substitutable with XELJANZ (tablets and oral solution). Switching between XELJANZ and XELJANZ XR should be made by the healthcare provider. • Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions (5.8) and Adverse Reactions (6.1) ] . • Interrupt use of XELJANZ/XELJANZ XR if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions (5.1) ] . • Take XELJANZ/XELJANZ XR with or without food [see Clinical Pharmacology (12.3) ] . • Swallow XELJANZ XR whole and intact. Do not crush, split, or chew the extended-release tablets [see Clinical Pharmacology (12.3) ] . 2.3 Recommended Dosage in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis Table 1 displays the recommended dosage of XELJANZ tablets and XELJANZ XR (extended-release tablets) for adults with RA, PsA, and AS [see Indication and Usage (1.1 , 1.2 , 1.3) ] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations (8.6 , 8.7 )] . The table also displ

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions (5.1) ] • Increased Risk of Mortality [see Warnings and Precautions (5.2) ] • Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3) ] • Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4) ] • Thrombosis [see Warnings and Precautions (5.5) ] • Gastrointestinal Perforations [see Warnings and Precautions (5.6) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.7) ] • Laboratory Abnormalities [see Warnings and Precautions (5.8) ] Most common adverse reactions are: • RA, PsA, and AS : Reported in ≥2% of adult patients treated with XELJANZ tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache. ( 6.1 ) • PcJIA : Consistent with common adverse reactions reported in adult patients with RA. ( 6.1 ) • UC : Reported in ≥ 5% of adult patients treated with either XELJANZ tablets and ≥1% greater than reported in patients treated with placebo: nasopharyngitis, elevated cholesterol levels, headache, URI, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. The clinical studies described in this subsection were conducted using XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) and/or XELJANZ oral solution. Adverse Reactions in Adults with Rheumatoid Arthritis In RA Safety Study 1, 1,455 adults were treated with XELJANZ 5 mg twice daily, 1,456 adults were treated with 10 mg twice daily, and 1,451 adults were treated with a TNF blocker for a median of 4 years [see Clinical Studies (14.6) ] . A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA because of increased risks [see Dosage and Administration (2.3) and Warnings and Precautions (5) ] . For the treatment of adults with moderately to severely active RA [see Indications and Usage (1.1) ] , the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily. The safety of XELJANZ was also evaluated in two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials in patients with RA. In these trials, adults were randomized to receive: • XELJANZ (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), • In combination with DMARDs (including methotrexate), XELJANZ 5 mg twice daily (1044 patients) or 10 mg twice daily (1043 patients and • Placebo (809 patients). All seven trials included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ groups were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure. The long-term safety population includes all adults with RA who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1) ] . The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for XELJANZ-treated patients and 3% for placebo-treated patients. Overall Infections In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respe

7 DRUG INTERACTIONS 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 Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with XELJANZ/XELJANZ XR is not recommended [see Clinical Pharmacology, Figure 3 (12.3) ] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; concomitant use of XELJANZ/XELJANZ XR with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, AS, UC, or pcJIA. Intervention Concomitant use with XELJANZ/XELJANZ XR is not recommended [see Indications and Usage (1) , Clinical Pharmacology, Figure 3 (12.3) ] See FPI for clinically significant drug interactions. ( 2 , 7 )