Upadacitinib

1 INDICATIONS AND USAGE RINVOQ/RINVOQ LQ is a Janus kinase (JAK) inhibitor. RINVOQ is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers. ( 1.1 ) Limitations of Use RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.1 ) RINVOQ/RINVOQ LQ is indicated for the treatment of adults and pediatric patients 2 years of age and older with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. ( 1.2 ) Limitation s of Use RINVOQ/RINVOQ LQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.2 ) RINVOQ is indicated for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable. ( 1.3 ) Limitations of Use RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants. ( 1.3 ) RINVOQ is indicated for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more TNF blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ. ( 1.4 ) Limitations of Use RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for UC, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.4 ) RINVOQ is indicated for the treatment of adults with moderately to severely active Crohn’s disease (CD) who have had an inadequate response or intolerance to one or more TNF blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ. ( 1.5 ) Limitations of Use RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for CD, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.5 ) RINVOQ is indicated for the treatment of adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blockers. ( 1.6 ) Limitations of Use RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.6 ) RINVOQ is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation who have had an inadequate response or intolerance to TNF blocker therapy. ( 1.7 ) Limitations of Use RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.7 ) RINVOQ/RINVOQ LQ is indicated for the treatment of patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. ( 1.8 ) Limitations of Use RINVOQ/RINVOQ LQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.8 ) RINVOQ is indicated for the treatment of adults with giant cell arteritis ( 1.9 ) Limitations of Use RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. ( 1.9 ) 1.1 Rheumatoid Arthritis RINVOQ ® is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine. 1.2 Psoriatic Arthritis RINVOQ/RINVOQ LQ is indicated for the treatment of adults and pediatric patients 2 years of age and older with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: RINVOQ/RINVOQ LQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. 1.3 Atopic Dermatitis RINVOQ is indicated for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable. Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants. 1.4 Ulcerative Colitis RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more TNF blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ. Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for UC, or with potent immunosuppressants such as azathioprine and cyclosporine. 1.5 Crohn’s Disease RINVOQ is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease (CD) who have had an inadequate response or intolerance to one or more TNF blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ. Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for CD, or with potent immunosuppressants such as azathioprine and cyclosporine. 1. 6 Ankylosing Spondylitis RINVOQ is indicated for the treatment of adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. 1. 7 Non-radiographic Axial Spondyloarthritis RINVOQ is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation who have had an inadequate response or intolerance to TNF blocker therapy. Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. 1.8 Polyarticular Juvenile Idiopathic Arthritis RINVOQ/RINVOQ LQ is indicated for the treatment of patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: RINVOQ/RINVOQ LQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. 1.9 Giant Cell Arteritis RINVOQ is indicated for the treatment of adults with giant cell arteritis. Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

2 DOSAGE AND ADMINISTRATION RINVOQ LQ oral solution is not substitutable with RINVOQ extended-release tablets ( 2.2 , 2.10 ). Changes between RINVOQ LQ oral solution and RINVOQ extended-release tablets should be made by the healthcare provider. Prior to treatment update immunizations and consider evaluating for active and latent tuberculosis, viral hepatitis, hepatic function, and pregnancy status ( 2.1 ) Avoid initiation or interrupt RINVOQ/RINVOQ LQ if absolute lymphocyte count is less than 500 cells/mm 3 , absolute neutrophil count is less than 1000 cells/mm 3 , or hemoglobin level is less than 8 g/dL. ( 2.1 , 2.14 ) Rheumatoid Arthritis , Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis Adults: The recommended dosage of RINVOQ is 15 mg once daily. ( 2.3 , 2.8 , 2.9 ) Psoriatic Arthritis Pediatric Patients 2 to less than 18 Years of Age Weighing at Least 10 kg: The recommended dosage is based on body weight ( 2.4 ) Adults: The recommended dosage of RINVOQ is 15 mg once daily. ( 2.4 ) Atopic Dermatitis Pediatric Patients 12 Years of Age and Older Weighing at Least 40 kg and Adults Less Than 65 Years of Age : Initiate treatment with RINVOQ 15 mg orally once daily. If an adequate response is not achieved, consider increasing the dosage to 30 mg orally once daily. ( 2.5 ) Adults 65 Years of Age and Older : Recommended dosage of RINVOQ is 15 mg once daily. ( 2.5 ) Severe Renal Impairment : Recommended dosage of RINVOQ is 15 mg once daily. ( 2.12 ) Ulcerative Colitis Adults: The recommended induction dosage of RINVOQ is 45 mg once daily for 8 weeks. The recommended maintenance dosage of RINVOQ is 15 mg once daily. A maintenance dosage of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease. Discontinue RINVOQ if adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response. ( 2.6 ) See the Full Prescribing Information for the recommended dosage in patients with renal or hepatic impairment and for dosage modification due to drug interactions. ( 2.12 , 2.13 ) Crohn’s D isease Adults: The recommended induction dosage of RINVOQ is 45 mg once daily for 12 weeks. The recommended maintenance dosage of RINVOQ is 15 mg once daily. A maintenance dosage of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response. ( 2.7 ) See the Full Prescribing Information for the recommended dosage in patients with renal or hepatic impairment and for dosage modification due to drug interactions. ( 2.12 , 2.13 ) Polyarticular Juvenile Idiopathic Arthritis The recommended dosage is based on body weight ( 2.10 ) Giant Cell Arteritis The recommended dosage of RINVOQ is 15 mg once daily in combination with a tapering course of corticosteroids. RINVOQ 15 mg once daily can be used as monotherapy following discontinuation of corticosteroids ( 2.11 ) 2.1 Recommended Evaluations and Immunizations Prior to Treatment Initiation Prior to RINVOQ/RINVOQ LQ treatment initiation, consider performing the following evaluations: Active and latent tuberculosis (TB) infection evaluation - If positive, treat for TB prior to RINVOQ/RINVOQ LQ use [see Warnings and Precautions ( 5.1 )] . Viral hepatitis screening in accordance with clinical guidelines – RINVOQ/RINVOQ LQ initiation is not recommended in patients with active hepatitis B or hepatitis C [see Warnings and Precautions ( 5.1 )] . A complete blood count – RINVOQ/RINVOQ LQ initiation is not recommended in patients with an absolute lymphocyte count less than 500 cells/mm 3 , absolute neutrophil count less than 1000 cells/mm 3 , or hemoglobin level less than 8 g/dL [see Dosage and Administration ( 2.14 ) and Warnings and Precautions ( 5.8 )] . Baseline hepatic function: RINVOQ/RINVOQ LQ initiation is not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]. Pregnancy Status: Verify the pregnancy status of females of reproductive potential prior to starting treatment [see Warnings and Precautions ( 5.9 ) and Use in Specific Populations ( 8.1 , 8.3 )]. Update immunizations according to current immunization guidelines [see Warnings and Precautions ( 5.10 )]. 2.2 Important Administration Instructions RINVOQ LQ oral solution is not substitutable with RINVOQ extended-release tablets [see Dosage and Administration ( 2.4 , 2.10 )]. Changes between RINVOQ LQ oral solution and RINVOQ extended-release tablets should be made by the health care provider. RINVOQ/RINVOQ LQ should be taken orally with or without food [see Clinical Pharmacology ( 12.3 )]. RINVOQ tablets should be swallowed whole. RINVOQ tablets should not be split, crushed, or chewed. RINVOQ LQ should be administered using the provided press-in bottle adapter and oral dosing syringe [see Instructions for Use ] . RINVOQ LQ is dosed twice daily [see Dosage and Administration ( 2.4 , 2.10 )]. 2.3 Recommended Dosage in Rheumatoid Arthritis The recommended dosage of RINVOQ is 15 mg once daily. 2. 4 Recommended Dosage in Psoriatic Arthritis Pediatric Patients 2 to Less Than 18 Years of Age The recommended dosage is based on body weight ( Table 1 ). Table 1: RINVOQ/RINVOQ LQ Dosage for Pediatric Patients 2 Years to Less Than 18 Years of Age with Psoriatic Arthritis Patient Weight RINVOQ LQ RINVOQ 10 kg to less than 20 kg 3 mg (3 mL oral solution) twice daily Not recommended 20 kg to less than 30 kg 4 mg (4 mL oral solution) twice daily Not recommended 30 kg and greater 6 mg (6 mL oral solution) twice daily 15 mg (one 15 mg tablet) once daily RINVOQ LQ oral solution is not substitutable with RINVOQ extended-release tablets. Changes between RINVOQ LQ oral solution and RINVOQ extended-release tablets should be made by the health care provider. Adults 18 Years of Age and Older The recommended dosage of RINVOQ is 15 mg once daily. 2.5 Recommended Dosage in Atopic Dermatitis Pediatric Patients 12 Years of Age and Older Weighing at Least 40 kg and Adults Less Than 65 Years of Age Initiate treatment with RINVOQ 15 mg once daily. If an adequate response is not achieved, consider increasing the dosage to 30 mg once daily. Discontinue RINVOQ if an adequate response is not achieved with the 30 mg dose. Use the lowest effective dose needed to maintain response. Adults 65 Years of Age and Older The recommended dosage of RINVOQ is 15 mg once daily. 2.6 Recommended Dosage in Ulcerative Colitis Adult Patients: Induction The recommended induction dosage of RINVOQ is 45 mg once daily for 8 weeks. Adult Patients: Maintenance The recommended dosage of RINVOQ for maintenance treatment is 15 mg once daily. A dosage of 30 mg once daily may be considered for patients with refractory, severe or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response. 2.7 Recommended Dosage in Crohn’s Disease Adult Patients: Induction The recommended induction dosage of RINVOQ is 45 mg once daily for 12 weeks. Adult Patients: Maintenance The recommended dosage of RINVOQ for maintenance treatment is 15 mg once daily. A dosage of 30 mg once daily may be considered for patients with refractory, severe or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response. 2. 8 Recommended Dosage in Ankylosing Spondylitis The recommended dosage of RINVOQ is 15 mg once daily. 2. 9 Recommend ed Dosage in Non-radiographic Axial Spondyloarthritis The recommended dosage of RINVOQ is 15 mg once daily. 2. 10 Recommended Dosage in Polyarticular Juvenile Idiopathic Arthritis The recommended dosage is based on body weight (Table 2). Table 2: RINVOQ/RINVOQ LQ Dosage for Patients 2 years and older with pJIA Patient Weight RINVOQ LQ RINVOQ 10 kg to less than 20 kg 3 mg (3 mL oral solution) twice daily Not recommended 20 kg to less than 30 kg 4 mg (4 mL oral solution) twice daily Not recommended 30 kg and greater 6 mg (6 mL oral solution) twice daily 15 mg (one 15 mg tablet) once daily RINVOQ LQ oral solution is not substitutable with RINVOQ extended-release tablets. Changes between RINVOQ LQ oral solution and RINVOQ extended-release tablets should be made by the health care provider. 2.11 Recommended Dosage in Giant Cell Arteritis The recommended dosage of RINVOQ is 15 mg once daily in combination with a tapering course of corticosteroids. RINVOQ 15 mg once daily can be used as monotherapy following discontinuation of corticosteroids. 2.1 2 Recommended Dosage in Patients with Renal Impairment or Hepatic Impairment Renal Impairment Rheumatoid Arthritis , Psoriatic Arthritis , Ankylosing Spondylitis , Non-radiographic Axial Spondyloarthritis , pJIA , and Giant Cell Arteritis : No dosage adjustment is needed for patients with mild, moderate, or severe renal impairment. Atopic Dermatitis: For patients with severe renal impairment [estimated glomerular filtration rate (eGFR) 15 to < 30 mL/min/1.73m 2 ] the recommended dosage of RINVOQ is 15 mg once daily [see Use in Specific Populations ( 8.6 )]. No dosage adjustment is needed for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m 2 ). RINVOQ is not recommended for use in patients with end stage renal disease (eGFR < 15 mL/min/1.73m 2 ) [see Use in Specific Populations ( 8.6 )]. Ulcerative Colitis: For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m 2 ), the recommended dosage of RINVOQ is: • Induction: 30 mg once daily for 8 weeks • Maintenance: 15 mg once daily No dosage adjustment is needed for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m 2 ). RINVOQ is not recommended for use in patients with end stage renal disease (eGFR < 15 mL/min/1.73m 2 ) [see Use in Specific Populations ( 8.6 )] . Crohn’s Disease: For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m 2 ), the recommended dosage of RINVOQ is: • Induction: 30 mg once daily for 12 weeks • Maintenance: 15 mg once daily No dosage adjustment is needed for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m 2 ). RINVOQ is not recommended for use in patients with end stage renal disease (eGFR < 15 mL/min/1.73m 2 ) [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment RINVOQ/RINVOQ LQ is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations ( 8.7 )] . Rheumatoid Arthritis , Psoriatic Arthritis , Atopic Dermatitis , Ankylosing Spondylitis , Non-radiographic Axial Spondyloarthritis , pJIA , and Giant Cell Arteritis : No dosage adjustment is needed for patients with mild or moderate hepatic impairment (Child-Pugh A or B). Ulcerative Colitis: For patients with mild to moderate hepatic impairment (Child-Pugh A or B) the recommended dosage of RINVOQ is: Induction: 30 mg once daily for 8 weeks Maintenance: 15 mg once daily Crohn’s Disease: For patients with mild to moderate hepatic impairment (Child-Pugh A or B) the recommended dosage of RINVOQ is: Induction: 30 mg once daily for 12 weeks Maintenance: 15 mg once daily 2. 1 3 Dosage Modifications Due to Drug Interactions Rheumatoid Arthritis, Psoriatic Arthritis, Ankylos ing Spondylitis , Non-radiographic Axial Spondyloarthritis , pJIA , and Giant Cell Arteritis No dosage adjustment is needed in patients receiving strong CYP3A4 inhibitors [see Drug Interactions ( 7.1 )] . Atopic Dermatitis The recommended dosage of RINVOQ in patients receiving strong CYP3A4 inhibitors is 15 mg once daily [see Drug Interactions ( 7.1 )] . Ulcerative Colitis The recommended dosage of RINVOQ in patients with ulcerative colitis receiving strong CYP3A4 inhibitors [see Drug Interactions ( 7.1 )]: Induction: 30 mg once daily for 8 weeks Maintenance: 15 mg once daily Crohn’s Disease The recommended dosage of RINVOQ in patients with Crohn’s disease receiving strong CYP3A4 inhibitors [see Drug Interactions ( 7.1 )] : Induction: 30 mg once daily for 12 weeks Maintenance: 15 mg once daily 2. 1 4 Dosage Interruption Infections If a patient develops a serious infection, including serious opportunistic infection, interrupt RINVOQ/RINVOQ LQ treatment until the infection is controlled [see Warnings and Precautions ( 5.1 )] . Laboratory Abnormalities Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 3 [see Warnings and Precautions ( 5.8 )] . Table 3: Recommended Dosage Interruptions for Laboratory Abnormalities Laboratory Measure Action Absolute Neutrophil Count (ANC) Interrupt treatment if ANC is less than 1000 cells/mm 3 ; treatment may be restarted once ANC returns above this value Absolute Lymphocyte Count (ALC) Interrupt treatment if ALC is less than 500 cells/mm 3 ; treatment may be restarted once ALC returns above this value Hemoglobin (Hb) Interrupt treatment if Hb is less than 8 g/dL; treatment may be restarted once Hb returns above this value Hepatic transaminases Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 )] 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 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Gastrointestinal Perforations [see Warnings and Precautions ( 5.7 )] Laboratory Abnormalities [see Warnings and Precautions ( 5.8 )] Rheumatoid arthritis , psoriatic arthritis , ankylosi ng spondylitis , and n on-radiographic a xial s pondyloarthritis : Adverse reactions (≥ 1%) were: upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, and headache. ( 6.1 ) Giant cell arteritis : Adverse reactions (≥ 5%) are upper respiratory tract infections, headache, fatigue, peripheral edema, cough, anemia, rash, herpes zoster, and nausea. ( 6.1 ) Atopic d ermatitis : Adverse reactions (≥ 1%) are: upper respiratory tract infections, acne, herpes simplex, headache, blood creatine phosphokinase increased, cough, hypersensitivity, folliculitis, nausea, abdominal pain, pyrexia, increased weight, herpes zoster, influenza, fatigue, neutropenia, myalgia, and influenza like illness. ( 6.1 ) Ulcerative colitis : Adverse reactions (≥ 5%) reported during induction or maintenance are: upper respiratory tract infections, increased blood creatine phosphokinase, acne, neutropenia, elevated liver enzymes, pyrexia, and rash. ( 6.1 ) Crohn’s disease : Adverse reactions (≥ 5%) reported during induction or maintenance are: upper respiratory tract infections, anemia, pyrexia, acne, herpes zoster, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Patients with Rheumatoid Arthritis A total of 3833 adult patients with rheumatoid arthritis were treated with RINVOQ 15 mg or upadacitinib 30 mg tablets once daily in the Phase 3 clinical trials of whom 2806 were exposed for at least one year. Patients could advance or switch to RINVOQ 15 mg from placebo, or be rescued to RINVOQ from active comparator or placebo from as early as Week 12 depending on the trial design. A total of 2630 patients received at least 1 dose of RINVOQ 15 mg, of whom 1860 were exposed for at least one year. In trials RA-I, RA-II, RA-III and RA-V, 1213 patients received at least 1 dose of RINVOQ 15 mg, of which 986 patients were exposed for at least one year, and 1203 patients received at least 1 dose of upadacitinib 30 mg, of which 946 were exposed for at least one year. Table 4: Adverse Reactions Reported in ≥ 1% of Rheumatoid Arthritis Patients Treated with RINVOQ 15 mg in Placebo-controlled Trials Adverse Reaction Placebo RINVOQ 15 mg N = 1042 (%) N = 1035 (%) Upper respiratory tract infection (URTI)* 9.5 13.5 Nausea 2.2 3.5 Cough 1.0 2.2 Pyrexia 0 1.2 *URTI includes: acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, viral upper respiratory tract infection Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg group and at a higher rate than in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (includes oral herpes), and oral candidiasis. Four integrated datasets are presented in the Specific Adverse Reaction section: Placebo-controlled Trials: Trials RA-III, RA-IV, and RA-V were integrated to represent safety through 12/14 weeks for placebo (n=1042) and RINVOQ 15 mg (n=1035). Trials RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), RINVOQ 15 mg (n=385), and upadacitinib 30 mg (n=384). Trial RA-IV did not include the 30 mg dose and, therefore, safety data for upadacitinib 30 mg can only be compared with placebo and RINVOQ 15 mg rates from pooling trials RA-III and RA-V. MTX-controlled Trials: Trials RA-I and RA-II were integrated to represent safety through 12/14 weeks for MTX (n=530), RINVOQ 15 mg (n=534), and upadacitinib 30 mg (n=529). 12-Month Exposure Dataset: Trials RA-I, II, III, and V were integrated to represent the long-term safety of RINVOQ 15 mg (n=1213) and upadacitinib 30 mg (n=1203). Exposure adjusted incidence rates were adjusted by trial for all the adverse events reported in this section. Specific Adverse Reactions Infections Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, infections were reported in 218 patients (95.7 per 100 patient-years) treated with placebo and 284 patients (127.8 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, infections were reported in 99 patients (136.5 per 100 patient-years) treated with placebo, 118 patients (164.5 per 100 patient-years) treated with RINVOQ 15 mg, and 126 patients (180.3 per 100 patient-years) treated with upadacitinib 30 mg. MTX-controlled Trials: Infections were reported in 127 patients (119.5 per 100 patient-years) treated with MTX monotherapy, 104 patients (91.8 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 128 patients (115.1 per 100 patient-years) treated with upadacitinib 30 mg monotherapy. 12-Month Exposure Dataset: Infections were reported in 615 patients (83.8 per 100 patient-years) treated with RINVOQ 15 mg and 674 patients (99.7 per 100 patient-years) treated with upadacitinib 30 mg. Serious Infections Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, serious infections were reported in 6 patients (2.3 per 100 patient-years) treated with placebo, and 12 patients (4.6 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, serious infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 7 patients (8.2 per 100 patient-years) treated with upadacitinib 30 mg. MTX-controlled Trials: Serious infections were reported in 2 patients (1.6 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 8 patients (6.4 per 100 patient-years) treated with upadacitinib 30 mg monotherapy. 12-Month Exposure Dataset: Serious infections were reported in 38 patients (3.5 per 100 patient-years) treated with RINVOQ 15 mg and 59 patients (5.6 per 100 patient-years) treated with upadacitinib 30 mg. The most frequently reported serious infections were pneumonia and cellulitis. Tuberculosis Placebo-controlled Trials and MTX-controlled Trials: In the placebo-controlled period, there were no active cases of tuberculosis reported in the placebo, RINVOQ 15 mg, and upadacitinib 30 mg groups. In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, RINVOQ 15 mg monotherapy, and upadacitinib 30 mg monotherapy groups. 12-Month Exposure Dataset: Active tuberculosis was reported for 2 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg. Cases of extra-pulmonary tuberculosis were reported. Opportunistic Infections (excluding tuberculosis) Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, opportunistic infections were reported in 3 patients (1.2 per 100 patient-years) treated with placebo, and 5 patients (1.9 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, opportunistic infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 6 patients (7.1 per 100 patient-years) treated with upadacitinib 30 mg. MTX-controlled Trials: Opportunistic infections were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 0 patients treated with RINVOQ 15 mg monotherapy, and 4 patients (3.2 per 100 patient-years) treated with upadacitinib 30 mg monotherapy. 12-Month Exposure Dataset: Opportunistic infections were reported in 7 patients (0.6 per 100 patient-years) treated with RINVOQ 15 mg and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg. Malignancies Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, malignancies excluding NMSC were reported in 1 patient (0.4 per 100 patient-years) treated with placebo, and 1 patient (0.4 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, malignancies excluding NMSC were reported in 0 patients treated with placebo, 1 patient (1.1 per 100 patient-years) treated with RINVOQ 15 mg, and 3 patients (3.5 per 100 patient-years) treated with upadacitinib 30 mg. MTX-controlled Trials: Malignancies excluding NMSC were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 0 patients treated with upadacitinib 30 mg monotherapy. 12-Month Exposure Dataset: Malignancies excluding NMSC were reported in 13 patients (1.2 per 100 patient-years) treated with RINVOQ 15 mg and 14 patients (1.3 per 100 patient-years) treated with upadacitinib 30 mg. Gastrointestinal Perforations Placebo-controlled Trials: There were no gastrointestinal perforations (based on medical review) reported in patients treated with placebo, RINVOQ 15 mg, and upadacitinib 30 mg. MTX-controlled Trials: There were no cases of gastrointestinal perforations reported in the MTX and RINVOQ 15 mg group through 12/14 weeks. Two cases of gastrointestinal perforations were observed in the upadacitinib 30 mg group. 12-Month Exposure Dataset: Gastrointestinal perforations were reported in 1 patient treated with RINVOQ 15 mg and 4 patients treated with upadacitinib 30 mg. Thrombosis Placebo-controlled Trials: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in 1 patient treated with placebo and 1 patient treated with RINVOQ 15 mg. In RA-V, venous thrombosis was observed in 1 patient treated with RINVOQ 15 mg. There were no observed cases of venous thrombosis reported in RA-III. No cases of arterial thrombosis were observed through 12/14 weeks. MTX-controlled Trials: In RA-II, venous thrombosis was observed in 0 patients treated with MTX monotherapy, 1 patient treated with RINVOQ 15 mg monotherapy and 0 patients treated with upadacitinib 30 mg monotherapy through Week 14. In RA-II, no cases of arterial thrombosis were observed through 12/14 weeks. In RA-I, venous thrombosis was observed in 1 patient treated with MTX, 0 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg through Week 24. In RA-I, arterial thrombosis was observed in 1 patient treated with upadacitinib 30 mg through Week 24. 12-Month Exposure Dataset: Venous thrombosis events were reported in 5 patients (0.5 per 100 patient-years) treated with RINVOQ 15 mg and 4 patients (0.4 per 100 patient-years) treated with upadacitinib 30 mg. Arterial thrombosis events were reported in 0 patients treated with RINVOQ 15 mg and 2 patients (0.2 per 100 patient-years) treated with upadacitinib 30 mg. Laboratory Abnormalities Hepatic Transaminase Elevations In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ 15 mg, and in 1.5% and 0.7% of patients treated with placebo, respectively. In RA-III and RA-V, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 1.0% of patients treated with RINVOQ 15 mg, 1.0% and 0% of patients treated with upadacitinib 30 mg and in 1.3% and 1.0% of patients treated with placebo, respectively. In MTX-controlled trials, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with RINVOQ 15 mg, 1.7% and 1.3% of patients treated with upadacitinib 30 mg and in 1.9% and 0.9% of patients treated with MTX, respectively. Lipid Elevations Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Elevations in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In controlled trials, for up to 12/14 weeks, changes from baseline in lipid parameters in patients treated with RINVOQ 15 mg and upadacitinib 30 mg, respectively, are summarized below: Mean LDL cholesterol increased by 14.81 mg/dL and 17.17 mg/dL. Mean HDL cholesterol increased by 8.16 mg/dL and 9.01 mg/dL. The mean LDL/HDL ratio remained stable. Mean triglycerides increased by 13.55 mg/dL and 14.44 mg/dL. Creatine Phosphokinase Elevations In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the RINVOQ 15 mg and placebo groups, respectively. Most elevations >5 x ULN were transient and did not require treatment discontinuation. In RA-III and RA-V, CPK elevations > 5 x ULN were observed in 0.3% of patients treated with placebo, 1.6% of patients treated with RINVOQ 15 mg, and none in patients treated with upadacitinib 30 mg. Neutropenia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in neutrophil counts, below 1000 cells/mm 3 in at least one measurement occurred in 1.1% and <0.1% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in neutrophil counts below 1000 cells/mm 3 in at least one measurement occurred in 0.3% of patients treated with placebo, 1.3% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical trials, treatment was interrupted in response to ANC less than 1000 cells/mm 3 . Lymphopenia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in lymphocyte counts below 500 cells/mm 3 in at least one measurement occurred in 0.9% and 0.7% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in lymphocyte counts below 500 cells/mm 3 in at least one measurement occurred in 0.5% of patients treated with placebo, 0.5% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. Anemia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in <0.1% of patients in both the RINVOQ 15 mg and placebo groups. In RA-III and RA-V, hemoglobin decreases below 8 g/dL in at least one measurement were observed in 0.3% of patients treated with placebo, and none in patients treated with RINVOQ 15 mg and upadacitinib 30 mg. Adverse Reactions in Patients with Psoriatic Arthritis A total of 1827 adult patients with psoriatic arthritis were treated with RINVOQ 15 mg or upadacitinib 30 mg tablets once daily in clinical trials, representing 1639.2 patient-years of exposure, of whom 722 were exposed to upadacitinib for at least one year. In the two Phase 3 trials, 907 patients received at least 1 dose of RINVOQ 15 mg, of whom 359 were exposed for at least one year. Two placebo-controlled trials were integrated (640 patients on RINVOQ 15 mg once daily and 635 patients on placebo) to evaluate the safety of RINVOQ 15 mg in comparison to placebo for up to 24 weeks after treatment initiation. Overall, the safety profile observed in patients with active psoriatic arthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequencies of herpes zoster and herpes simplex were ≥1% (1.1% and 1.4%, respectively) with RINVOQ 15 mg and 0.8% and 1.3%, respectively with placebo. A higher incidence of acne and bronchitis was also observed in patients treated with RINVOQ 15 mg (1.3% and 3.9%, respectively) compared to placebo (0.3% and 2.7%, respectively). Adverse Reactions in Patients with Atopic Dermatitis Three Phase 3 (AD-1, AD-2, and AD-3) and one Phase 2b (AD-4) randomized, double-blind, placebo-controlled, multicenter trials evaluated the safety of RINVOQ in patients with moderate-to-severe atopic dermatitis. The majority of patients were White (68%) and male (57%). The mean age was 34 years (ranged from 12 to 75 years) and 13% of the patients were 12 to less than 18 years. In these 4 trials, 2612 patients were treated with RINVOQ 15 mg tablets or 30 mg tablets orally once daily, with or without concomitant topical corticosteroids (TCS). In the Phase 3 clinical trials (AD-1, AD-2, and AD-3), a total of 1239 patients received RINVOQ 15 mg, of whom 791 were exposed for at least one year and 1246 patients received RINVOQ 30 mg, of whom 826 were exposed for at least one year. Trials AD-1, AD-2, and AD-4 compared the safety of RINVOQ monotherapy to placebo through Week 16. Trial AD-3 compared the safety of RINVOQ + TCS to placebo + TCS through Week 16. Weeks 0 to 16 (Trials AD-1 to AD-4) In RINVOQ trials with and without TCS (Trials AD-1, 2, 3 and 4) through Week 16, the proportion of patients who discontinued treatment because of adverse reactions in the RINVOQ 15 mg, 30 mg and placebo groups were 2.3%, 2.9% and 3.8%, respectively. Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% in the RINVOQ 15 mg or 30 mg groups during the first 16 weeks of treatment. Table 5: Adverse Reactions Reported in ≥ 1% of Patients with Atopic Dermatitis Treated with RINVOQ 15 mg or 30 mg Adverse Reaction Placebo RINVOQ 15 mg RINVOQ 30 mg N = 902 (%) N = 899 (%) N = 906 (%) Upper respiratory tract infection (URTI)* 17 23 25 Acne** 2 10 16 Herpes simplex*** 2 4 8 Headache 4 6 6 Increased blood creatine phosphokinase 2 5 6 Cough 1 3 3 Hypersensitivity**** 2 2 3 Folliculitis 1 2 3 Nausea 1 3 3 Abdominal pain***** 1 3 2 Pyrexia 1 2 2 Increased Weight 1 2 2 Herpes zoster****** 1 2 2 Influenza <1 2 2 Fatigue 1 1 2 Neutropenia <1 1 2 Myalgia 1 1 2 Influenza like illness 1 1 2 * Includes: laryngitis, laryngitis viral, nasopharyngitis, oropharyngeal pain, pharyngeal abscess, pharyngitis, pharyngitis streptococcal, pharyngotonsillitis, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinolaryngitis, sinusitis, tonsillitis, tonsillitis bacterial, upper respiratory tract infection, viral pharyngitis, viral upper respiratory tract infection ** Includes: acne and dermatitis acneiform *** Includes: genital herpes, genital herpes simplex, herpes dermatitis, herpes ophthalmic, herpes simplex, nasal herpes, ophthalmic herpes simplex, herpes virus infection, oral herpes **** Includes anaphylactic reaction, anaphylactic shock, angioedema, dermatitis exfoliative generalized, drug hypersensitivity, eyelid oedema, face oedema, hypersensitivity, periorbital swelling, pharyngeal swelling, swelling face, toxic skin eruption, type I hypersensitivity, urticaria ***** Includes abdominal pain and abdominal pain upper ****** Includes herpes zoster and varicella Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg and/or 30 mg group and at a higher rate than in the placebo group through Week 16 included anemia, oral candidiasis, pneumonia, non-melanoma skin cancer, and the adverse event of retinal detachment. The safety profile of RINVOQ through Week 52 was generally consistent with the safety profile observed at Week 16. Overall, the safety profile observed in patients with AD treated with RINVOQ was similar to the safety profile in patients with RA. Other specific adverse reactions that were reported in patients with AD included eczema herpeticum/Kaposi’s varicelliform eruption. Eczema Herpeticum/Kaposi’s Varicelliform Eruption Placebo-controlled Period (16 weeks): Eczema herpeticum was reported in 4 patients (1.6 per 100 patient-years) treated with placebo, 6 patients (2.2 per 100 patient-years) treated with RINVOQ 15 mg and 7 patients (2.6 per 100 patient-years) treated with RINVOQ 30 mg. 12-Month Exposure (Weeks 0 to 52): Eczema herpeticum was reported in 18 patients (1.6 per 100 patient-years) treated with RINVOQ 15 mg and 17 patients (1.5 per 100 patient-years) treated with RINVOQ 30 mg. Adverse Reactions in Patients with Ulcerative Colitis RINVOQ was studied up to 8 weeks in patients with moderately to severely active ulcerative colitis in two randomized, double-blind, placebo-controlled induction studies (UC-1, UC-2) and a randomized, double-blind, placebo controlled, dose-finding study (UC-4; NCT02819635). Long term safety up to 52-weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (UC-3) and a long-term extension study [see Clinical Studies ( 14.4 )] . In the two induction studies (UC-1, UC-2) and a dose finding study (UC-4), 1097 patients were enrolled of whom 719 patients received RINVOQ 45 mg tablets once daily. In the maintenance study (UC-3), 746 patients were enrolled of whom 250 patients received RINVOQ 15 mg tablets once daily and 251 patients received RINVOQ 30 mg tablets once daily. Adverse reactions reported in ≥2% of patients in any treatment arm in the induction and maintenance studies are shown in Tables 6 and 7, respectively. Table 6: Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with RINVOQ 45 mg in Placebo-Controlled Induction Studies (UC-1, UC-2 and UC-4) Adverse Reaction Placebo RINVOQ 45 mg Once Daily N = 378 (%) N = 719 (%) Upper respiratory tract infection* 7 9 Acne* 1 6 Increased blood creatine phosphokinase 1 5 Neutropenia* <1 5 Rash* 1 4 Elevated liver enzymes** 2 3 Lymphopenia* 1 3 Folliculitis 1 2 Herpes simplex* <1 2 * Composed of several similar terms ** Elevated liver enzymes composed of elevated ALT, AST, GGT, ALP, liver transaminases, hepatic enzymes, bilirubin, drug-induced liver injury and cholestasis. Other adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 8 included herpes zoster and pneumonia. Table 7: Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with RINVOQ 15 mg or 30 mg in the Placebo-Controlled Maintenance Study (UC-3) 1 Adverse Reaction Placebo RINVOQ 15 mg Once Daily RINVOQ 30 mg Once Daily N = 245 (%) N = 250 (%) N = 251 (%) Upper respiratory tract infection* 18 17 20 Increased blood creatine phosphokinase 2 6 8 Pyrexia 3 3 6 Neutropenia* 2 3 6 Elevated liver enzymes** 1 6 4 Rash* 4 5 5 Herpes zoster 0 5 6 Folliculitis 2 2 4 Hypercholesterolemia* 1 2 4 Influenza 1 3 3 Herpes simplex* 1 2 3 Lymphopenia* 2 3 2 Hyperlipidemia* 0 2 2 1 Patients who were responders to 8 weeks induction therapy with RINVOQ 45 mg once daily * Composed of several similar terms ** Elevated liver enzymes composed of elevated ALT, AST, GGT, ALP, liver transaminases, hepatic enzymes, bilirubin, drug-induced liver injury, and cholestasis. The adverse reaction of non-melanoma skin cancer was reported in 1% of patients in the RINVOQ 30 mg group and none of the patients in the RINVOQ 15 mg or placebo group through Week 52. The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods. Overall, the safety profile observed in patients with ulcerative colitis treated with RINVOQ was generally similar to the safety profile in patients with RA and AD. Specific Adverse Reactions Serious Infections Induction Studies: In UC-1, UC-2, and UC-4, serious infections were reported in 5 patients (8.4 per 100 patient-years) treated with placebo and 9 patients (8.4 per 100 patient-years) treated with RINVOQ 45 mg through 8 weeks. Placebo-controlled Maintenance Study: In UC-3, serious infections were reported in 8 patients (5.9 events per 100 patient-years) treated with placebo, 9 patients (5.0 events per 100 patient-years) treated with RINVOQ 15 mg, and 8 patients (3.7 events per 100 patient-years) treated with RINVOQ 30 mg through 52 weeks. Laboratory Abnormalities Hepatic Transaminase Elevations In studies UC-1, UC-2, and UC-4, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 1.5% of patients treated with RINVOQ 45 mg, and 0% of patients treated with placebo for 8 weeks. AST elevations to ≥ 3 x ULN occurred in 1.5% of patients treated with RINVOQ 45 mg, and 0.3% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN occurred in 0.4% of patients treated with RINVOQ 45 mg and 0% of patients treated with placebo. In UC-3, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 4.4% of patients treated with RINVOQ 30 mg, 2% of patients treated with RINVOQ 15 mg, and 1.2% of patients treated with placebo for 52 weeks. Elevations of AST to ≥ 3 x ULN in at least one measurement were observed in 2% of patients treated with RINVOQ 30 mg, 1.6% of patients treated with RINVOQ 15 mg and 0.4% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN were observed in 1.2% of patients treated with 30 mg, 0.4% of patients treated with 15 mg, and 0.4% of patients treated with placebo. Overall, laboratory abnormalities observed in patients with ulcerative colitis treated with RINVOQ were similar to those described in patients with RA. Adverse Reactions in Patients with Crohn’s Disease RINVOQ was studied up to 12 weeks in patients with moderately to severely active CD in two randomized, double-blind, placebo-controlled induction studies (CD-1, CD-2). Long term safety up to 52 weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (CD-3), with additional data provided from a long-term extension (LTE) period [see Clinical Studies ( 14.5 )] . In the two induction studies (CD-1, CD-2), 1021 patients were enrolled, of whom 674 patients received RINVOQ 45 mg tablets once daily during the placebo-controlled period. In the maintenance study (CD-3), 673 patients were enrolled, of whom 221 patients received RINVOQ 15 mg tablets once daily and 229 patients received RINVOQ 30 mg tablets once daily during the randomized, placebo-controlled period. Overall, the safety profile observed in patients with Crohn’s disease treated with RINVOQ was consistent with the known safety profile for RINVOQ in other indications. Adverse reactions reported in ≥2% of patients treated with RINVOQ and at a higher rate than placebo in the induction and maintenance studies are shown in Tables 8 and 9, respectively. Table 8: Adverse Reactions Reported in ≥2% of Patients with Crohn’s Disease Treated with RINVOQ 45 mg in Placebo-Controlled Induction Studies (CD-1 and CD-2) Adverse Reaction Placebo RINVOQ 45 mg Once Daily N = 347 (%) N = 674 (%) Upper respiratory tract infection* 8 13 Anemia* 6 7 Acne* 2 6 Pyrexia 3 4 Increased blood creatine phosphokinase 1 3 Influenza 1 3 Herpes simplex* 1 3 Leukopenia* 1 2 Neutropenia* <1 2 Herpes zoster 0 2 * Composed of several similar terms Adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 12 included folliculitis, hypercholesterolemia, bronchitis, pneumonia, oral candidiasis, and hyperlipidemia. Table 9: Adverse Reactions Reported in ≥2% of Patients with Crohn’s Disease Treated with RINVOQ 15 mg or 30 mg in the Placebo-Controlled Maintenance Study (CD-3) 1 Adverse Reaction Placebo RINVOQ 15 mg Once Daily RINVOQ 30 mg Once Daily N = 223 (%) N = 221 (%) N = 229 (%) Upper respiratory tract infection* 11 14 12 Pyrexia 2 3 7 Herpes zoster* 2 3 5 Headache* 1 3 5 Acne* 3 2 5 Gastroenteritis* 2 3 3 Fatigue 2 3 3 Increased blood creatine phosphokinase 1 2 3 Elevated liver enzymes 2 <1 2 3 Leukopenia* <1 1 2 Neutropenia* <1 1 2 Bronchitis* 0 1 2 Pneumonia* 1 4 1 Cough 2 3 1 1 Patients who were responders to 12 weeks induction therapy with RINVOQ 45 mg once daily. 2 Elevated liver enzymes includes alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, transaminases increased, blood bilirubin increased. * Composed of several similar terms Adverse reactions reported in less than 2% of patients in the RINVOQ 15 mg or 30 mg group and at a higher rate than in the placebo group through Week 52 included hyperlipidemia, oral candidiasis, and hypercholesterolemia. The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods. Specific Adverse Reactions Serious Infections Induction Studies: In CD-1 and CD-2, serious infections were reported in 6 patients (8 per 100 patient-years) treated with placebo and 13 patients (9 per 100 patient-years) treated with RINVOQ 45 mg through 12 weeks of the placebo-controlled period. Maintenance Study/LTE: In the long-term placebo-controlled period, serious infections were reported in 10 patients (7 per 100 patient-years) treated with placebo, 7 patients (4 per 100 patient-years) treated with RINVOQ 15 mg, and 13 patients (6 per 100 patient-years) treated with RINVOQ 30 mg. Gastrointestinal Perforations Induction Studies: During the induction studies in all patients treated with RINVOQ 45 mg (N=938), gastrointestinal perforation was reported in 4 patients (2 per 100 patient-years). In the placebo-controlled induction period, in CD-1 and CD-2, gastrointestinal perforation was reported in no patients treated with placebo (N=347) and 1 patient (1 per 100 patient-years) treated with RINVOQ 45 mg (N=674) through 12 weeks. Maintenance Study/LTE: In the long-term placebo-controlled period, gastrointestinal perforation was reported in 1 patient (1 per 100 patient-years) treated with placebo, 1 patient (<1 per 100 patient-years) treated with RINVOQ 15 mg, and 1 patient (<1 per 100 patient-years) treated with RINVOQ 30 mg. Patients who received placebo or RINVOQ 15 mg for maintenance therapy and lost response were treated with rescue RINVOQ 30 mg (N=336). Among these patients, gastrointestinal perforation was reported in 3 patients (1 per 100 patient-years) through long-term treatment. Adverse Reactions in Patients with Ankylosing Spondylitis A total of 596 patients with ankylosing spondylitis were treated with RINVOQ 15 mg tablets in the two clinical trials representing 577.3 patient-years of exposure, of whom 220 were exposed to RINVOQ 15 mg for at least one year. Overall, the safety profile observed in patients with active ankylosing spondylitis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis and psoriatic arthritis. During the 14-week placebo-controlled period in Trial AS-I, the frequency of headache was 5.4% with RINVOQ 15 mg and 2.1% with placebo. During the 14-week placebo-controlled period in Trial AS-II, the frequency of headache was 3.3% with RINVOQ 15 mg and 1.4% with placebo. Adverse Reactions in Patients with Non-radiographic Axial Spondyloarthritis A total of 187 patients with non-radiographic axial spondyloarthritis were treated with RINVOQ 15 mg tablets in the clinical trial representing 116.6 patient-years of exposure, of whom 31 were exposed to RINVOQ 15 mg for at least one year. Overall, the safety profile observed in patients with active non-radiographic axial spondyloarthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Adverse Reactions in Patients with Polyarticular Juvenile Idiopathic Arthritis A total of 83 pediatric patients with juvenile idiopathic arthritis (JIA) with active polyarthritis were treated with RINVOQ/RINVOQ LQ in the clinical trial, representing 123.7 patient-years of exposure, of whom 48 were exposed to RINVOQ/RINVOQ LQ for at least one year. Overall, the safety profile observed in pediatric patients with JIA with active polyarthritis treated with RINVOQ/RINVOQ LQ was consistent with the known safety profile of RINVOQ. Adverse Reactions in Patients with Giant Cell Arteritis In the Phase 3 study, 209 patients with giant cell arteritis received at least 1 dose of RINVOQ 15 mg, of whom 122 were exposed for at least one year during the 52-week placebo-controlled period. The safety profile observed in patients with giant cell arteritis was generally consistent with the known safety profile for RINVOQ. Table 10: Adverse Reactions Reported in ≥ 5% of Patients with Giant Cell Arteritis Treated with RINVOQ 15 mg in the Placebo-controlled Study Adverse Reaction Placebo RINVOQ 15 mg N = 112 (%) N = 209 (%) Upper respiratory tract infection (URTI) a 20.5 21.5 Headache 11.6 16.3 Fatigue 5.4 9.1 Peripheral edema b 2.7 8.6 Cough c 3.6 7.2 Anemia d 2.7 6.7 Rash e 2.7 5.7 Herpes zoster f 2.7 5.3 Nausea 3.6 5.3 a Includes acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, viral pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, viral upper respiratory tract infection, upper respiratory tract infection b Includes edema and edema peripheral c Includes cough and productive cough d Includes anemia, iron deficiency anemia, blood iron decreased, hemoglobin decreased, mean cell volume increased e Includes rash, rash erythematous, rash macular, rash maculo-papular, rash vesicular f Includes herpes zoster, herpes zoster oticus, ophthalmic herpes zoster Specific Adverse Reactions Opportunistic Infections (excluding tuberculosis and herpes zoster ) In the 52-week placebo-controlled period, opportunistic infections were reported in 1 patient (1.1 per 100 patient-years) treated with placebo and 4 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg. Thromb osis In the 52-week placebo-controlled period, venous thromboembolic events (pulmonary embolism or deep vein thrombosis) were observed in 4 patients (4.3 per 100 patient-years) treated with placebo and 7 patients (3.9 per 100 patient-years) treated with RINVOQ 15 mg. Events of arterial thrombosis were observed in 2 patients (1.1 per 100 patient-years) treated with RINVOQ 15 mg and 0 patients treated with placebo.

12.3 Pharmacokinetics Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. After a single dose administration of RINVOQ 15 mg, 30 mg, and 45 mg tablets under fasting condition in healthy subjects, mean C max was 31.6 ng/mL, 71.8 ng/mL, and 90.7 ng/mL, respectively, and mean AUC inf was 265 ng·h/mL, 543 ng·h/mL, and 752 ng·h/mL, respectively. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after once daily administration. Following the administration of the recommended pediatric dosage ( Table 1 , Table 2 ) in pJIA and psoriatic arthritis patients, the mean steady-state C max is predicted to be 47.6 ng/mL and the mean steady-state AUC 0-24 is predicted to be 342 ng·h/mL. Upadacitinib pharmacokinetics are comparable between rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and giant cell arteritis patients. RINVOQ tablets and RINVOQ LQ are not bioequivalent; therefore, the 2 dosage forms are not interchangeable on a milligram-per-milligram basis [ see Dosage and Administration ( 2.2 )] . Absorption Following oral administration of RINVOQ extended-release tablets, upadacitinib is absorbed with a median T max of 2 to 4 hours. Following oral administration of 6 mg RINVOQ LQ, upadacitinib is absorbed with a median T max of 1 hour. Coadministration of RINVOQ tablets with a high-fat/high-calorie meal had no clinically relevant effect on upadacitinib exposures (increased AUC inf by 29% and C max by 39% to 60%). Coadministration of RINVOQ LQ with food is not expected to have a clinically relevant effect on upadacitinib exposure [see Dosage and Administration ( 2.2 )] . Distribution Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components with a blood to plasma ratio of 1.0. Elimination Metabolism Upadacitinib metabolism is mediated by mainly CYP3A4 with a potential minor contribution from CYP2D6. The pharmacologic activity of upadacitinib is attributed to the parent molecule. In a human radiolabeled study, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma while the main metabolite detected (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib. Excretion Following single dose administration of [ 14 C]-upadacitinib immediate-release solution, upadacitinib was eliminated predominantly as the unchanged parent drug in urine (24%) and feces (38%). Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminal elimination half-life ranged from 8 to 14 hours. Specific Populations Body Weight, Gender, and Race Body weight, gender, race, and ethnicity did not have a clinically meaningful effect on upadacitinib exposure in adult patient populations. Pediatric Patients In pediatric patients with JIA with active polyarthritis, upadacitinib clearance increased with increasing body weight. Age (over the range of 2 to < 18 years old) had no additional effect on upadacitinib pharmacokinetics after accounting for the effect of body weight. Upadacitinib plasma exposures in pediatric patients with pJIA and psoriatic arthritis following the recommended pediatric dosage are predicted to be comparable to those observed in adult patients with rheumatoid arthritis and psoriatic arthritis, respectively. No meaningful difference in the systemic exposure of upadacitinib was observed in pediatric patients with atopic dermatitis 12 years of age and older weighing at least 40 kg compared to adults. Geriatric Patients No clinically meaningful differences in the pharmacokinetics of upadacitinib were observed in geriatric patients (≥ 65 years of age) compared to younger adult patients. Patients with Renal Impairment Upadacitinib mean AUC inf after a single dose administration of 15 mg upadacitinib tablets was 18%, 33%, and 44% higher in patients with mild (eGFR 60 to < 90 mL/min/1.73 m 2 ), moderate (eGFR 30 to < 60 mL/min/1.73 m 2 ), and severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 ), respectively, compared to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ). Upadacitinib mean C max was similar among subjects with normal and impaired renal function. In patients receiving RINVOQ/RINVOQ LQ, mild and moderate renal impairment is not expected to have a clinically relevant effect on upadacitinib exposure [see Dosage and Administration ( 2.12 ) and Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment Upadacitinib mean AUC inf after a single dose administration of 15 mg upadacitinib tablets was 28% and 24% higher in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib mean C max was unchanged in patients with mild hepatic impairment and 43% higher in patients with moderate hepatic impairment compared to subjects with normal liver function. Upadacitinib was not studied in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration ( 2.12 ) and Use in Specific Populations ( 8.7 )] . Drug Interaction Studies Potential for Other Drugs to Influence the Pharmacokinetics of Upadacitinib Upadacitinib is metabolized in vitro by CYP3A4 with a minor contribution from CYP2D6. The effect of co-administered drugs on upadacitinib plasma exposures is provided in Table 11 [see Drug Interactions ( 7 )] . Table 11: Change in Pharmacokinetics of Upadacitinib in the Presence of Co-administered Drugs Co- administered Drug Regimen of Co- administered Drug Ratio (90% CI) a C max AUC Methotrexate 10 to 25 mg/week 0.97 (0.86-1.09) 0.99 (0.93- 1.06) Strong CYP3A4 inhibitor: Ketoconazole 400 mg once daily x 6 days 1.70 (1.55-1.89) 1.75 (1.62-1.88) Strong CYP3A4 inducer: Rifampin 600 mg once daily x 9 days 0.49 (0.44-0.55) 0.39 (0.37-0.42) OATP1B inhibitor: Rifampin 600 mg single dose 1.14 (1.02-1.28) 1.07 (1.01-1.14) CI: Confidence interval a Ratios for C max and AUC compare co-administration of the medication with upadacitinib vs. administration of upadacitinib alone. pH modifying medications (e.g., antacids or proton pump inhibitors) are not expected to affect upadacitinib plasma exposures based on in vitro assessments and population pharmacokinetic analyses. CYP2D6 metabolic phenotype had no effect on upadacitinib pharmacokinetics (based on population pharmacokinetic analyses), indicating that inhibitors of CYP2D6 have no clinically relevant effect on upadacitinib exposures. Potential for Upadacitinib to Influence the Pharmacokinetics of Other Drugs In vitro studies indicate that upadacitinib does not inhibit the activity of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at clinically relevant concentrations. In vitro studies indicate that upadacitinib induces CYP3A4 but does not induce CYP2B6 or CYP1A2 at clinically relevant concentrations. In vitro studies indicate that upadacitinib does not inhibit the transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations. Clinical studies indicate that upadacitinib has no clinically relevant effects on the pharmacokinetics of co-administered drugs. Following upadacitinib 30 mg and 45 mg tablets once daily, the effects on each CYP enzymes (CYP1A2, CYP3A, CYP2C9, and CYP2C19) were similar between two doses except for the effect on CYP2D6. Following upadacitinib 30 mg and 45 mg tablets once daily, a weak induction of CYP3A4 was observed. A weak inhibition of CYP2D6 was observed at upadacitinib 45 mg but not at 30 mg. Summary of results from clinical studies which evaluated the effect of upadacitinib on other drugs is provided in Table 12. Table 1 2 : Change in Pharmacokinetics of Co-administered Drugs or In Vivo Markers of CYP Activity in the Presence of Upadacitinib Co-administered Drug or CYP Activity Marker Multiple-Dose Regimen of Upadacitinib Ratio (90% CI) a C max AUC Methotrexate 6 mg to 24 mg BID b 1.03 (0.86-1.23) 1.14 (0.91-1.43) Sensitive CYP1A2 Substrate: Caffeine 45 mg QD c 1.05 (0.97-1.14) 1.04 (0.95-1.13) Sensitive CYP3A Substrate: Midazolam 30 mg QD c 0.74 (0.68-0.80) 0.74 (0.68-0.80) Sensitive CYP3A Substrate: Midazolam 45 mg QD c 0.75 (0.69 -0.83) 0.76 (0.69 -0.83) Sensitive CYP2D6 Substrate: Dextromethorphan 30 mg QD c 1.09 (0.98-1.21) 1.07 (0.95-1.22) Sensitive CYP2D6 Substrate: Dextromethorphan 45 mg QD c 1.30 (1.13-1.50) 1.35 (1.18-1.54) Sensitive CYP2C9 Substrate: S-Warfarin 45 mg QD c 1.18 (1.05-1.33) 1.12 (1.05-1.20) Sensitive CYP2C19 Marker: 5-OH Omeprazole to Omeprazole metabolic ratio 45 mg QD c -- 0.96 (0.90-1.02) CYP2B6 Substrate: Bupropion 30 mg QD c 0.87 (0.79-0.96) 0.92 (0.87-0.98) Rosuvastatin 30 mg QD c 0.77 (0.63-0.94) 0.67 (0.56-0.82) Atorvastatin 30 mg QD c 0.88 (0.79-0.97) 0.77 (0.70-0.85) Ethinylestradiol 30 mg QD c 0.96 (0.89-1.02) 1.11 (1.04-1.19) Levonorgestrel 30 mg QD c 0.96 (0.87-1.06) 0.96 (0.85-1.07) CYP: cytochrome P450; CI: Confidence interval; BID: twice daily; QD: once daily a Ratios for C max and AUC compare co-administration of the medication with upadacitinib vs. administration of medication alone. b Immediate-release formulation c Extended-release tablet formulation