Tofacitinib

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 not recommended. 1.2 Psoriatic Arthritis XELJANZ (tablets and oral solution) is indicated for the treatment of adult and pediatric patients 2 years of age and older with active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. XELJANZ XR (extended-release tablets) is indicated for the treatment of adults with active PsA who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of XELJANZ or XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.3 Ankylosing Spondylitis XELJANZ tablets and XELJANZ XR (extended-release tablets) are indicated for the treatment of adult patients with active ankylosing spondylitis (AS), 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 DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.4 Polyarticular Course Juvenile Idiopathic Arthritis XELJANZ (tablets and oral solution) are indicated for the treatment of pediatric patients 2 years of age and older with of 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 in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.5 Ulcerative Colitis XELJANZ tablets and XELJANZ XR (extended-release tablets) are indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of XELJANZ tablets or XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

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 displays the recommended dosage modifications for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] , and patients with lymphopenia, neutropenia, or anemia. Table 1: Recommended Dosage of XELJANZ Tablets and XELJANZ XR in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis Adults XELJANZ Tablets XELJANZ XR (extended-release tablets) Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ tablets/XELJANZ XR with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3 , ANC <1000 cells/mm 3 , or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. 5 mg twice daily 11 mg once daily Recommended Dosage in Patients with Renal Impairment (RI) Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft‑Gault equation: CLcr >80 mL/min (normal renal function); >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); <30 mL/min (severe renal impairment). Mild RI (CLcr >50 and ≤80 mL/min) 5 mg twice daily 11 mg once daily Moderate RI (CLcr ≥30 and ≤50 mL/min) 5 mg once daily XELJANZ tablets 5 mg once daily Severe RI (CLcr <30 mL/min) 5 mg once daily XELJANZ tablets 5 mg once daily For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) 5 mg twice daily 11 mg once daily Moderate HI (Child-Pugh B) 5 mg once daily XELJANZ tablets 5 mg once daily Severe HI (Child-Pugh C) Use of XELJANZ tablets/XELJANZ XR is not recommended. Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) 5 mg twice daily 11 mg once daily Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) 5 mg once daily XELJANZ tablets 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. Patients with ANC less than 500 cells/mm 3 Discontinue dosing. Patients with ANC 500 to 1000 cells/mm 3 Interrupt dosing. When ANC is greater than 1000, resume 5 mg twice daily. Interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily. Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets Patients treated with XELJANZ tablets 5 mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets 5 mg. 2.4 Recommended Dosage in Pediatric Patients 2 Years of Age and Older with Psoriatic Arthritis or Polyarticular Course Juvenile Idiopathic Arthritis Table 2 displays the recommended body weight-based dosages for XELJANZ tablets and XELJANZ oral solution in pediatric patients 2 years of age and older with PsA or pcJIA [see Indication and Usage (1.2 , 1.4) ] 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 includes recommended dosage modification for pediatric patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] , and pediatric patients with lymphopenia, neutropenia, or anemia. Administer XELJANZ oral solution using the included press-in bottle adapter and oral dosing syringe [see Instructions for Use ] . Table 2: Recommended Dosage of XELJANZ Tablets and XELJANZ Oral Solution in Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Pediatric Patients 2 Years of Age and Older XELJANZ tablets and XELJANZ oral solution Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ (tablets and oral solution) with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3 , ANC <1000 cells/mm 3 , or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. • 10 kg ≤ body weight <20 kg: 3.2 mg (3.2 mL oral solution) twice daily • 20 kg ≤ body weight <40 kg: 4 mg (4 mL oral solution) twice daily • Body weight ≥40 kg: 5 mg (one 5 mg tablet or 5 mL oral solution) twice daily Patients treated with XELJANZ oral solution 5 mL may be switched to XELJANZ tablets 5 mg. Recommended Dosage in Patients with Renal Impairment (RI) Mild RI Same as patients with normal renal function. Moderate RI • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily Severe RI • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI Same as patients with normal hepatic function. Moderate HI • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily Severe HI Use of XELJANZ tablets/XELJANZ oral solution is not recommended. Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended. Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. Patients with ANC less than 500 cells/mm 3 Discontinue dosing. Patients with ANC 500 to 1000 cells/mm 3 Interrupt dosing until ANC is greater than 1000 cells/mm 3 . Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. 2.5 Recommended Dosage in Adults with Ulcerative Colitis Table 3 displays the recommended dosage of XELJANZ tablets and XELJANZ XR (extended-release tablets) in adult patients with ulcerative colitis (UC) [see Indications and Usage (1.5) ] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations (8.6 , 8.7) ] . Table 4 displays the recommended dosage modification for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] , and patients with lymphopenia, neutropenia, or anemia. Table 3: Recommended Dosage of XELJANZ Tablets and XELJANZ XR in Adults with Ulcerative Colitis With and Without Renal Impairment or Hepatic Impairment Adults XELJANZ tablets XELJANZ XR (extended-release tablets) Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ tablets/XELJANZ XR with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3 , ANC <1000 cells/mm 3 , or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. Induction: 10 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 10 mg twice daily for a maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 22 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 22 mg once daily for a maximum of 16 weeks. Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg twice daily. For patients with loss of response during maintenance treatment, may consider a dosage of 10 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: 11 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 22 mg once daily (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. Recommended Dosage in Patients with Renal Impairment (RI) Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft‑Gault equation: CLcr >80 mL/min (normal renal function); CLcr >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); <30 mL/min (severe renal impairment). Mild RI (CLcr >50 and ≤80 mL/min) Same as patients with normal renal function. Moderate RI (CLcr ≥30 and ≤50 mL/min) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Severe RI (CLcr <30 mL/min) Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Maintenance: XELJANZ XR is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate or Severe RI. For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) Same as patients with normal hepatic function. Moderate HI (Child-Pugh B) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: XELJANZ XR is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate HI. Severe HI (Child-Pugh C) Use of XELJANZ tablets/XELJANZ XR is not recommended. Table 4: Dosage Modifications of XELJANZ Tablets and XELJANZ XR Due to Drug Interactions and for Lymphopenia, Neutropenia or Anemia in Adults with Ulcerative Colitis Adults XELJANZ Tablets XELJANZ XR (extended-release tablets) Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended. Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Strong CYP3A4 inhibitor(s) Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: XELJANZ XR is not recommended. see Maintenance Dosage for XELJANZ tablets for Strong CYP3A4 inhibitors. Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. ANC less than 500 cells/mm 3 Discontinue dosing. ANC 500 to 1000 cells/mm 3 If taking: • 10 mg twice daily, reduce to 5 mg twice daily. When ANC is greater than 1000, increase to 10 mg twice daily based on clinical response. • 5 mg twice daily, interrupt dosing. When ANC is greater than 1000, resume 5 mg twice daily. If taking: • 22 mg once daily, reduce to 11 mg once daily. When ANC is greater than 1000, increase to 22 mg once daily based on clinical response. • 11 mg once daily, interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily. Hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets Patients treated with XELJANZ tablets: • 5 mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets 5 mg. • 10 mg twice daily may be switched to XELJANZ XR extended-release tablets 22 mg once daily the day following the last dose of XELJANZ tablets 10 mg.

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, respectively). Serious Infections: In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined XELJANZ 5 mg twice daily and 10 mg twice daily group minus placebo. In the seven placebo-controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1) ] . Tuberculosis: In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, tuberculosis (TB) was not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily. In the seven placebo-controlled trials, during the 0 to 12 months exposure, TB was reported in 0 patients who received XELJANZ 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB was 10 months (range from 152 to 960 days) [see Warnings and Precautions (5.1) ]. Opportunistic Infections (excluding tuberculosis): In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily. In the seven placebo-controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) [see Warnings and Precautions (5.1) ]. Malignancies In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined XELJANZ 5 mg and 10 mg twice daily group minus placebo. In the seven placebo-controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 7 patients (0.6 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. One of these malignancies was a case of lymphoma that occurred during the 0-to-12-month period in a patient treated with XELJANZ 10 mg twice daily. The most common types of malignancy, including malignancies observed during the long-term extension in XELJANZ-treated patients, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma [see Warnings and Precautions (5.3) ]. Laboratory Abnormalities Lymphopenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in absolute lymphocyte counts below 500 cells/mm 3 occurred in 0.04% of patients for the XELJANZ 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure. Confirmed lymphocyte counts less than 500 cells/mm 3 were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.8) ]. Neutropenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in ANC below 1,000 cells/mm 3 occurred in 0.07% of patients for the XELJANZ 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure. There were no confirmed decreases in ANC below 500 cells/mm 3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections. In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials [see Warnings and Precautions (5.8) ]. Liver Enzyme Elevations: Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients with RA treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dosage, resulted in decrease or normalization of liver enzymes. In the placebo-controlled monotherapy trials (0–3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups. In the placebo-controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× ULN, which required hospitalizations and a liver biopsy. Lipid Elevations: In the placebo-controlled clinical trials in patients with RA, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the placebo-controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm. • Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm. • Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients. In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy. In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials. Serum Creatinine Elevations: In the placebo-controlled clinical trials in patients with RA, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however, with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown. Common Adverse Reactions Table 5 displays adverse reactions that occurred in 2% or more of patients on XELJANZ 5 mg or 10 mg twice daily and at least 1% greater than in XELJANZ-treated patients that observed in placebo-treated patients with or without DMARD in the RA trials. Table 5: Common Adverse Reactions reported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0–3 Months) Preferred Term Placebo XELJANZ 5 mg Twice Daily XELJANZ 10 mg Twice Daily The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily [see Dosage and Administration (2) ] . N = 809 (%) N = 1336 (%) N = 1349 (%) N reflects randomized and treated patients from the seven placebo-controlled clinical trials. Upper respiratory tract infection 3 4 4 Nasopharyngitis 3 4 3 Diarrhea 2 4 3 Headache 2 4 3 Hypertension 1 2 2 Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients [see Clinical Studies (14) ] . The safety experience in these patients was consistent with Studies RA-I through V. Adverse Reactions in Adults with Psoriatic Arthritis The safety of XELJANZ was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA): • Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months. • Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period. In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of PsA. For the treatment of adults with active PsA [see Indications and Usage (1.2) ] , the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily [see Dosage and Administration (2.3) ]. All patients in the clinical trials in patients with PsA were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (10%) patients aged 65 years or older and 66 (14%) patients with diabetes at baseline. During the 2 PsA controlled clinical trials, there were: • 3 malignancies (excluding NMSC) in 474 patients who received XELJANZ plus non-biologic DMARD (6 to 12 months exposure) • 0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and • 0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with XELJANZ. The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA. Adverse Reactions in Adults with Ankylosing Spondylitis The safety of XELJANZ was evaluated in adults with active ankylosing spondylitis (AS) in a double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II). • Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily. • Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS [see Indications and Usage (1.3) ] , the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily [see Dosage and Administration (2.3) ] . In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either XELJANZ 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3%) patients aged 65 years or older and 18 (4%) patients with diabetes at baseline. The safety profile observed in adults with AS treated with XELJANZ was consistent with the safety profile observed in adults with RA and PsA. Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis XELJANZ tablets and XELJANZ oral solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 pediatric patients from 2 years to 17 years of age in Study pcJIA-I [see Clinical Studies (14.4) ] and one open-label extension study (Study A3921145). The total patient exposure (defined as patients who received at least one dose of XELJANZ tablets or XELJANZ oral solution) was 105.6 patient-years in Study pcJIA-I and 777.5 patient-years in Study A3921145. In general, the types of adverse reactions in pediatric patients 2 years of age and older with pcJIA, were consistent with those seen in adults with RA and PsA (see Adverse Reactions in Adults with Rheumatoid Arthritis and Adverse Reactions in Adults with Psoriatic Arthritis ) . Adverse Reactions in Adults with Ulcerative Colitis The safety of XELJANZ has been evaluated in adults with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV) [see Clinical Studies (14.5) ] . Adverse reactions reported in ≥5% of patients treated with either XELJANZ 5 mg or 10 mg twice daily and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials of patients with UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. Induction Trials in Adults with UC Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater in XELJANZ-treated patients than placebo-treated patients in the 3 induction trials of patients with UC (Studies UC-I, UC-II, and UC-V) were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia. Maintenance Trial in Adults with UC Common adverse reactions reported in ≥4% of patients treated with either dosage of XELJANZ and ≥1% greater than reported in patients treated with placebo in the maintenance trial of patients with UC (Study UC-III) are shown in Table 6. Table 6: Common Adverse Reactions Reported in ≥4% of patients treated with either XELJANZ dosage and ≥1% greater in XELJANZ-treated patients than placebo-treated patients. in Adults with UC During the 52-Week Maintenance Trial (Study UC-III) Preferred Term Placebo XELJANZ 5 mg Twice Daily XELJANZ 10 mg Twice Daily N = 198 (%) N = 198 (%) N = 196 (%) Nasopharyngitis 6 10 14 Elevated cholesterol levels Includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased. 1 5 9 Headache 6 9 3 Upper respiratory tract infection 4 7 6 Increased blood creatine phosphokinase 2 3 7 Rash 4 3 6 Diarrhea 3 2 5 Herpes zoster 1 1 5 Gastroenteritis 3 3 4 Anemia 2 4 2 Nausea 3 1 4 Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC [see Warnings and Precautions (5.1 , 5.3) ] . During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1,220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients. In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily [see Warnings and Precautions (5.3) ] . Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer [see Warnings and Precautions (5.5) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed) Skin and subcutaneous tissue disorders: Acne

12.3 Pharmacokinetics Following oral administration of XELJANZ (tablets and oral solution), peak plasma concentrations were reached within 0.5 hour - 1 hour, elimination half-life was about 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dosage range. Steady state concentrations were achieved in 24-48 hours with negligible accumulation after twice daily administration. Following oral administration of XELJANZ XR (extended-release tablets), peak plasma concentrations were reached at 4 hours and half-life was about 6 to 8 hours. Steady state concentrations were achieved within 48 hours with negligible accumulation after once daily administration. Table 8 describes the pharmacokinetic parameters of XELJANZ and XELJANZ XR. Table 8: Pharmacokinetic Parameters of XELJANZ/XELJANZ XR Following Multiple Oral Dosing PK Parameters Values represent the geometric mean, except T max , for which is the median (range) is shown. (CV%) XELJANZ XELJANZ XR Dosing Regimen 5 mg Twice Daily 10 mg Twice Daily 11 mg Once Daily 22 mg Once Daily Abbreviations: AUC 24 = area under the concentration time profile from time 0 to 24 hours; C max = maximum plasma concentration; C min = minimum plasma concentration; T max = time to C max ; CV = Coefficient of variation. AUC 24 (ng.hr/mL) 263.4 (15) 539.6 (22) 269.0 (18) 596.6 (19) C max (ng/mL) 42.7 (26) 84.7 (18) 38.2 (15) 83.8 (25) C min (ng/mL) 1.41 (40) 3.10 (54) 1.07 (69) 3.11 (43) T max (hours) 1.0 (0.5 to14.0 Values beyond 12 hours were after the evening dose which was administered 12 hours after the morning dose of twice-daily XELJANZ. ) 0.8 (0.5 to 14.0 ) 4.0 (3.0 to 4.0) 4.0 (2.0 to 4.0) Absorption XELJANZ The absolute oral bioavailability of XELJANZ is 74%. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while C max was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals [see Dosage and Administration (2.2) ] . XELJANZ XR Coadministration of XELJANZ XR 11 and 22 mg with a high-fat meal resulted in no changes in AUC while C max was increased by 27% and 19% respectively. T max was extended by approximately 1 hour for both XELJANZ XR 11 and 22 mg. Distribution After intravenous administration, the volume of distribution was 87 L. The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. Metabolism and Excretion Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule. Pharmacokinetics in Patients with RA, PsA, AS, and UC Population pharmacokinetic (PK) analyses indicated that PK characteristics were similar between patients with RA, PsA, ankylosing spondylitis, and UC. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 9). Table 9: Tofacitinib Exposure in Patients with RA, PsA, AS, and UC After Administration of XELJANZ 5 mg Twice Daily or 10 mg Twice Daily Pharmacokinetic Parameters Pharmacokinetic parameters estimated based on population pharmacokinetic analysis. Geometric Mean (CV%) XELJANZ 5 mg Twice Daily XELJANZ 10 mg Twice Daily Rheumatoid Arthritis Psoriatic Arthritis Ankylosing Spondylitis Ulcerative Colitis Ulcerative Colitis Abbreviations: AUC 0–24,ss = area under the plasma concentration-time curve over 24 hours at steady state; CV = coefficient of variation. AUC 0–24 , ss (ng∙h/mL) 504 (22.0%) 419 (34.1%) 381 (25.4%) 423 (22.6%) 807 (24.6%) Specific Populations Covariate evaluation as part of population PK analyses in adult patient populations indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, biological sex and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (C max ) and lower trough (C min ) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. Covariate evaluation as part of population PK analyses in pediatric patients with pcJIA, including PsA, identified body weight significantly impacting tofacitinib exposure, which supports weight-based dosing in this population. There were no identified clinically significant differences in tofacitinib exposure with different age, biological sex, racial, or pcJIA or PsA disease severity groups. The effect of renal and hepatic impairment and other intrinsic factors on the PK of tofacitinib is shown in Figure 1. Figure 1: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics Note: Reference values for weight, age, biological sex, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are patients with normal renal and hepatic function. Renal function was estimated using creatinine clearance by Cockcroft-Gault method and hepatic function was estimated using Child-Pugh scoring method. In patients with end-stage renal disease maintained on hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib [see Dosage and Administration (2.3 , 2.4 , 2.5) and Use in Specific Populations (8.6) ] . Figure 1 Drug Interaction Studies Potential for XELJANZ/XELJANZ XR to Influence the PK of Other Drugs In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations corresponding to the steady state C max of a 10 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when concomitantly administered with XELJANZ. In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state C max of a 10 mg twice daily dose. In patients with RA, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in patients with RA. Therefore, concomitant use with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in patients with RA. In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low. The impact of tofacitinib on the PK of other drugs for the concomitant drugs are shown in Figure 2. Figure 2: Impact of Tofacitinib on the Pharmacokinetics of Other Drugs Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion. Figure 2 Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the pharmacokinetics of tofacitinib (see Figure 3 ). Figure 3: Impact of Other Drugs on the Pharmacokinetics of Tofacitinib Note: Reference group is administration of XELJANZ alone. Figure 3