Upadacitinib

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.

RINVOQ extended-release tablets: 15 mg upadacitinib: purple, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a15’ on one side. 30 mg upadacitinib: red, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a30’ on one side. 45 mg upadacitinib: yellow to mottled yellow, biconvex oblong, with dimensions of 14 x 8 mm, and debossed with ‘a45’ on one side. RINVOQ LQ oral solution: 1 mg/mL upadacitinib; clear, colorless to light yellow solution in bottle of 180 mL. RINVOQ extended-release tablets: 15 mg, 30 mg, and 45 mg ( 3 ) RINVOQ LQ oral solution: 1 mg/mL ( 3 )

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 )

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 ) Hypoglycemia in Patients with Diabetes: Consider increased monitoring of blood glucose; advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia. ( 5.8 ) Laboratory Abnormalities : Monitoring recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. ( 5.9 ) 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. ( 5.10 , 8.1 , 8.3 ) Vaccinations : Avoid use with live vaccines. ( 5.11 ) 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. ( 5.12 )

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. […]

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 )] Hypoglycemia in Patients with Diabetes [see Warnings and Precautions ( 5.8 )] Laboratory Abnormalities [see Warnings and Precautions ( 5.9 )] 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. […]

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.

Lactation : Advise not to breastfeed. ( 8.2 ) Hepatic Impairment : RINVOQ/RINVOQ LQ is not recommended in patients with severe hepatic impairment. ( 8.7 )

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).

8.2 Lactation Risk Summary There are no data on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see Data ). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with RINVOQ/RINVOQ LQ, and for 6 days (approximately 10 half-lives) after the last dose. Data A single oral dose of 10 mg/kg radiolabeled upadacitinib was administered to lactating female Sprague-Dawley rats on post-partum days 7-8. Drug exposure was approximately 30-fold greater in milk than in maternal plasma based on AUC 0-t values. Approximately 97% of drug-related material in milk was parent drug.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ/RINVOQ LQ [see Use in Specific Populations ( 8.1 )] . Contraception Females Based on animal studies, upadacitinib may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )] . Advise female patients of reproductive potential to use effective contraception during treatment with RINVOQ/RINVOQ LQ and for 4 weeks after the final dose.

8.4 Pediatric Use Ankylosing Spondylitis , Non-radiographic Axial Spondyloarthritis , Ulcerative Colitis, and Crohn’s Disease The safety and effectiveness of RINVOQ/RINVOQ LQ in pediatric patients with ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, or Crohn’s disease have not been established. Polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis The safety and effectiveness of RINVOQ/RINVOQ LQ in pediatric patients 2 to less than 18 years of age with pJIA and psoriatic arthritis have been established. […]

Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Upadacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In a cell-free isolated enzyme assay, upadacitinib had greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2. In human leukocyte cellular assays, upadacitinib inhibited cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 more potently than JAK2/JAK2 mediated STAT phosphorylation. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.