Rinvoq

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.

4 CONTRAINDICATIONS RINVOQ/RINVOQ LQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients [see Warnings and Precautions ( 5.6 )] . Known hypersensitivity to upadacitinib or any of the excipients in RINVOQ/RINVOQ LQ. ( 4 , 5.6 )

5 WARNINGS AND PRECAUTIONS Serious Infections : Avoid use in patients with active, serious infection, including localized infections. ( 5.1 ) Hypersensitivity : Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. Discontinue if a serious hypersensitivity reaction occurs. ( 5.6 ) Gastrointestinal (GI) Perforations : Monitor patients at risk for GI perforations and promptly evaluate patients with symptoms. ( 5.7 ) Laboratory Abnormalities : Monitoring recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. ( 5.8 ) Embryo-Fetal Toxicity : May cause fetal harm based on animal studies. Advise female patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 ) Vaccinations : Avoid use with live vaccines. ( 5.10 ) Medication Residue in Stool : Observed in stool or ostomy output in patients with shortened GI transit times. Monitor patients clinically and consider alternative treatment if inadequate therapeutic response. ( 5.11 ) 5.1 Serious Infections Serious and sometimes fatal infections have been reported in patients receiving RINVOQ. The most frequent serious infections reported with RINVOQ included pneumonia and cellulitis [see Adverse Reactions ( 6.1 )] . Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis, were reported with RINVOQ. A higher rate of serious infections was observed with RINVOQ 30 mg compared to RINVOQ 15 mg. Avoid use of RINVOQ/RINVOQ LQ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating RINVOQ/RINVOQ LQ in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ/RINVOQ LQ. Interrupt RINVOQ/RINVOQ LQ if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with RINVOQ/RINVOQ LQ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and RINVOQ/RINVOQ LQ should be interrupted if the patient is not responding to antimicrobial therapy. RINVOQ/RINVOQ LQ may be resumed once the infection is controlled. Tuberculosis Evaluate and test patients for latent and active tuberculosis (TB) infection prior to administration of RINVOQ/RINVOQ LQ. Patients with latent TB should be treated with standard antimycobacterial therapy before initiating RINVOQ/RINVOQ LQ. RINVOQ/RINVOQ LQ should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of RINVOQ/RINVOQ LQ in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. During RINVOQ/RINVOQ LQ use, monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Viral R eactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, were reported in clinical trials with RINVOQ [see Adverse Reactions ( 6.1 )] . The risk of herpes zoster appears to be higher in patients treated with RINVOQ in Japan. If a patient develops herpes zoster, consider temporarily interrupting RINVOQ/RINVOQ LQ until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed in accordance with clinical guidelines before starting and during therapy with RINVOQ/RINVOQ LQ. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA, were excluded from clinical trials. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical trials. However, cases of hepatitis B reactivation were still reported in patients enrolled in the Phase 3 trials of RINVOQ. If hepatitis B virus DNA is detected while receiving RINVOQ/RINVOQ LQ, a liver specialist should be consulted. 5.2 Mortality In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ/RINVOQ LQ. 5. 3 Malignancy and Lymphoproliferative Disorders Malignancies, including lymphomas, were observed in clinical trials of RINVOQ [see Adverse Reactions ( 6.1 )] . In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ/RINVOQ LQ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers. Non-Melanoma Skin Cancer NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen. 5.4 Major Adverse Cardiovascular Events In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ/RINVOQ LQ, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue RINVOQ/RINVOQ LQ in patients that have experienced a myocardial infarction or stroke. 5. 5 Thrombosis Thromboses, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death [see Adverse Reactions ( 6.1 )] . In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers. If symptoms of thrombosis occur, patients should discontinue RINVOQ/RINVOQ LQ and be evaluated promptly and treated appropriately. Avoid RINVOQ/RINVOQ LQ in patients that may be at increased risk of thrombosis. 5. 6 Hypersensitivity Reactions Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ/RINVOQ LQ and institute appropriate therapy [see Adverse Reactions ( 6.1 )] . 5. 7 Gastrointestinal Perforations Gastrointestinal perforations have been reported in clinical trials with RINVOQ [see Adverse Reactions ( 6.1 ) ] . Monitor RINVOQ/RINVOQ LQ-treated patients who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis and those taking concomitant medications including NSAIDs or corticosteroids). Evaluate promptly patients presenting with new onset abdominal pain for early identification of gastrointestinal perforation. 5.8 Laboratory Abnormalities Neutropenia Treatment with RINVOQ was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm 3 ). Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid RINVOQ/RINVOQ LQ initiation and interrupt RINVOQ/RINVOQ LQ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm 3 ) [see Dosage and Administration ( 2.1 , 2.14 )] . Lymphopenia ALC less than 500 cells/mm 3 were reported in RINVOQ-treated patients in clinical trials. Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid RINVOQ/RINVOQ LQ initiation or interrupt RINVOQ/RINVOQ LQ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm 3 ) [see Dosage and Administration ( 2.1 , 2.14 )] . Anemia Decreases in hemoglobin levels to less than 8 g/dL were reported in RINVOQ-treated patients in clinical trials. Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid RINVOQ/RINVOQ LQ initiation or interrupt RINVOQ/RINVOQ LQ treatment in patients with a low hemoglobin level (i.e., less than 8 g/dL) [see Dosage and Administration ( 2.1 , 2.14 )] . Lipids Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol [see Adverse Reactions ( 6.1 )] . Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Assess lipid parameters approximately 12 weeks after initiation of treatment, and thereafter according to the clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for the management of hyperlipidemia. Liver Enzyme Elevations Treatment with RINVOQ was associated with increased incidence of liver enzyme elevations compared to treatment with placebo. Evaluate liver enzymes at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ/RINVOQ LQ should be interrupted until this diagnosis is excluded. 5. 9 Embryo-Fetal Toxicity Based on findings in animal studies, RINVOQ/RINVOQ LQ may cause fetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in fetal malformations. Verify the pregnancy status of patients of reproductive potential prior to starting treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with RINVOQ/RINVOQ LQ and for 4 weeks following completion of therapy [see Use in Specific Populations ( 8.1 , 8.3 )] . 5. 10 Vaccination s Avoid use of live vaccines during or immediately prior to RINVOQ/RINVOQ LQ therapy initiation. Prior to initiating RINVOQ/RINVOQ LQ treatment, it is recommended that patients be brought up to date with all immunizations, including prophylactic varicella zoster or herpes zoster vaccinations, in agreement with current immunization guidelines. 5.11 Medication Residue in Stool Reports of medication residue in stool or ostomy output have occurred in patients taking RINVOQ. Most reports described anatomic (e.g., ileostomy, colostomy, intestinal resection) or functional gastrointestinal conditions with shortened gastrointestinal transit times. Instruct patients to contact their healthcare provider if medication residue is observed repeatedly. Monitor patients clinically and consider alternative treatment if there is an inadequate therapeutic response.

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors : See the Full Prescribing Information for dosage modification for patients with atopic dermatitis, ulcerative colitis, and Crohn’s disease. ( 2.13 , 7.1 ) Strong CYP3A4 Inducers : Coadministration of RINVOQ/RINVOQ LQ with strong CYP3A4 inducers is not recommended. ( 7.2 ) 7.1 Strong CYP3A4 Inhibitors Upadacitinib exposure is increased when it is co-administered with a strong CYP3A4 inhibitor (such as ketoconazole, clarithromycin, and grapefruit), which may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Monitor patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondylarthritis, pJIA, or giant cell arteritis closely for adverse reactions when co-administering RINVOQ/RINVOQ LQ with strong CYP3A4 inhibitors. Food or drink containing grapefruit should be avoided during treatment with RINVOQ/RINVOQ LQ. For patients with atopic dermatitis, coadministration of RINVOQ 30 mg once daily with strong CYP3A4 inhibitors is not recommended. For patients with ulcerative colitis or Crohn’s disease taking strong CYP3A4 inhibitors, reduce the RINVOQ induction dosage to 30 mg once daily. The recommended maintenance dosage is 15 mg once daily [see Dosage and Administration ( 2.13 )] . 7.2 Strong CYP3A4 Inducers Upadacitinib exposure is decreased when it is co-administered with strong CYP3A4 inducers (such as rifampin), which may lead to reduced therapeutic effect [see Clinical Pharmacology ( 12.3 )] . Coadministration of RINVOQ/RINVOQ LQ with strong CYP3A4 inducers is not recommended.

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.

8.1 Pregnancy Pregnancy Surveillance Program There is a pregnancy surveillance program for RINVOQ/RINVOQ LQ that monitors pregnancy outcomes in women exposed to RINVOQ/RINVOQ LQ. If RINVOQ/RINVOQ LQ exposure occurs during pregnancy, healthcare providers or patients should report the pregnancy by calling 1-800-633-9110. Risk Summary Available data from the pharmacovigilance safety database and postmarketing case reports on use of RINVOQ in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. Based on animal studies, RINVOQ/RINVOQ LQ has the potential to adversely affect a developing fetus. Advise patients of reproductive potential and pregnant patients of the potential risk to the fetus. In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the 15 mg tablet dose, 0.8 and 7.6 times the 30 mg tablet dose, and 0.6 and 5.6 times the maximum recommended human dose (MRHD) of 45 mg (on an AUC basis) resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib during organogenesis at exposures approximately 0.29 and 2.2 times the 15 mg dose, 0.15 times and 1.1 times the 30 mg dose, and at 0.11 and 0.82 times the MRHD (on an AUC basis). In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 3 times the 15 mg dose, 1.4 times the 30 mg dose, and the same as the MRHD (on an AUC basis) resulted in no maternal or developmental toxicity ( see Data ) . The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages are 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or inflammatory bowel disease. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Data Animal Data In an oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 5, 25, and 75 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that consisted of misshapen humerus and bent scapula) at exposures equal to or greater than approximately 1.7 times the 15 mg tablet dose, 0.9 times the 30 mg tablet dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 5 mg/kg/day and higher). Additional skeletal malformations (bent forelimbs/hindlimbs and rib/vertebral defects) and decreased fetal body weights were observed in the absence of maternal toxicity at an exposure approximately 84 times the 15 mg dose, 43 times the 30 mg dose, and 31 times the MRHD (on an AUC basis at a maternal oral dose of 75 mg/kg/day). In a second oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 1.5 and 4 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that included bent humerus and scapula) at exposures approximately 1.6 times the 15 mg dose, 0.8 times the 30 mg dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 4 mg/kg/day). No developmental toxicity was observed in rats at an exposure approximately 0.29 times the 15 mg tablet dose, 0.15 times the 30 mg tablet dose, and 0.11 times the MRHD (on an AUC basis at a maternal oral dose of 1.5 mg/kg/day). In an oral embryo-fetal developmental study, pregnant rabbits received upadacitinib at doses of 2.5, 10, and 25 mg/kg/day during the period of organogenesis from gestation day 7 to 19. Embryolethality, decreased fetal body weights, and cardiovascular malformations were observed in the presence of maternal toxicity at an exposure approximately 15 times the 15 mg tablet dose, 7.6 times the 30 mg tablet dose, and 5.6 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both total and early resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 2.2 times the 15 mg tablet dose, 1.1 times the 30 mg tablet dose, and 0.82 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day). In an oral pre- and post-natal development study, pregnant female rats received upadacitinib at doses of 2.5, 5, and 10 mg/kg/day from gestation day 6 through lactation day 20. No maternal or developmental toxicity was observed in either mothers or offspring, respectively, at an exposure approximately 3 times the 15 mg tablet dose, 1.4 times the 30 mg tablet dose, and at approximately the same exposure as the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).