Methods of administering upadacitinib to avoid adverse drug interactions and effects

Abstract

The present disclosure is directed to methods for treating immune diseases and disorders with upadacitinib, comprising adjusting the dose of upadacitinib in patients with severe renal impairment, patients receiving concomitant strong inhibitors of cytochrome P450 3A4 (CYP3A4), and adult patients 65 years of age or older.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 299,324, filed January 13, 2022, and U.S. Provisional Patent Application No. 63 / 320,149, filed March 15, 2022, each of which is incorporated by reference in its entirety.

[0002] The present disclosure is directed to methods for treating diseases and disorders with upadacitinib. [Background technology]

[0003] Upadacitinib is a novel JAK1-selective inhibitor with minimal inhibitory effects on JAK2 and JAK3, which may potentially minimize some of the reported safety concerns with non-selective JAK inhibition that are believed to be mediated through inhibition of the JAK2 and JAK3 signaling pathways, such as asymptomatic, mild and reversible changes in infections including herpes zoster reactivation, malignancies, hemoglobin, lymphocyte count, white blood cell count, serum creatinine, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and hepatic transaminases (alanine transaminase [ALT], aspartate transaminase [AST]) and creatine phosphokinase (CPK). See Vermeire et al., "Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): Results from a phase 2, double-blind, randomized, placebo-controlled trial." Lancet 2017;389(10066):266-75; Fleischmann et al., "ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis." N Engl J Med. 2012;367(6):495-507.

[0004] JAK1 inhibition blocks the signaling of many important pro-inflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, and IL-15, which are known causes of inflammatory disorders. By modulating these pro-inflammatory cytokine pathways, upadacitinib may be an effective treatment for inflammatory or autoimmune disorders, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), giant cell arteritis (GCA), Takayasu's arteritis, polyarticular course juvenile idiopathic arthritis (pcJIA), Crohn's disease (CD), UC, and atopic dermatitis (AD). The clinical hypothesis is that based on the identified selectivity profile of JAK inhibition, upadacitinib may show an improved benefit / risk profile compared to other less selective JAK inhibitors or other treatment strategies for patients with inflammatory diseases.

[0005] To date, upadacitinib has been investigated in 22 Phase 1 studies in healthy volunteers (one of which also used a substudy in subjects with mild-to-moderate RA) and multiple Phase 2 or 3 studies for the indications of RA, CD, AD, PsA, and UC. Upadacitinib has been shown to be effective in treating the indicated medical conditions based on available data from various studies. Overall safety results showed that upadacitinib was well tolerated, with the type and frequency of AEs consistent with subjects with medical conditions receiving immunomodulatory therapy. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Vermeire et al., "Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): Results from a phase 2, double-blind, randomized, placebo-controlled trial." Lancet 2017; 389 (10066): 266-75 [Non-Patent Document 2] Fleischmann et al.; "ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis." N Engl J Med. 2012; Vol. 367 (Issue 6): pp. 495-507) Summary of the Invention [Problem to be solved by the invention]

[0007] Summary of the Invention As described herein, upadacitinib has been shown to be well tolerated and effective in multiple diseases and disorders in many clinical trials. During clinical development of upadacitinib, it was unexpectedly observed that the systemic exposure of upadacitinib may be increased or decreased with co-administration of certain therapeutic agents or in patients with renal insufficiency. In such cases, it may be desirable to adjust the dosage of upadacitinib or to avoid administration of therapeutic agents that alter the exposure level of upadacitinib. The present disclosure addresses these needs and provides methods for treating diseases and disorders with upadacitinib while avoiding potentially adverse interactions. [Means for solving the problem]

[0008] In one aspect, the disclosure provides a method of treating a patient receiving a strong CYP3A4 inhibitor concomitantly with upadacitinib, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0009] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient receiving a strong CYP3A4 inhibitor, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0010] In yet another aspect, there is provided a method of improving safety when administering upadacitinib to a patient receiving a strong CYP3A4 inhibitor, comprising the steps of: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0011] In a further aspect, the disclosure provides a method of reducing the occurrence or likelihood of an adverse event in treating a disease for which upadacitinib is clinically approved for treatment in a patient receiving a strong CYP3A4 inhibitor, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0012] In yet another aspect, the disclosure provides a method of treating an FDA-approved indication with upadacitinib in a patient receiving a strong CYP3A4 inhibitor, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0013] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib of 30 mg is administered without caution during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the daily dose of upadacitinib of 30 mg is administered during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib of 30 mg is administered as two 15 mg dosage forms.

[0014] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when a daily dose of 15 mg of upadacitinib is administered during the period when the patient is receiving a strong CYP3A4 inhibitor.

[0015] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0016] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0017] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient is administered a strong CYP3A4 inhibitor. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0018] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0019] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0020] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0021] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient receiving a strong CYP34A inhibitor, comprising: Determine the recommended daily dose of upadacitinib for patients not receiving a strong CYP34A inhibitor and select from 45 mg, 30 mg, or 15 mg; Reducing the recommended daily upadacitinib dose from 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose from 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0022] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient receiving a strong CYP34A inhibitor, comprising: assessing whether the patient is receiving a strong CYP34A inhibitor; Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0023] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient receiving a strong CYP3A4 inhibitor, comprising: determining the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor and selecting from 45 mg, 30 mg, or 15 mg; assessing whether the patient is receiving a strong CYP3A4 inhibitor; Reducing the recommended daily upadacitinib dose from 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; reducing the recommended daily upadacitinib dose from 30 mg to 15 mg while patients are receiving a strong CYP3A4 inhibitor; and Maintain the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0024] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib of 30 mg is administered without caution during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the daily dose of upadacitinib of 30 mg is administered during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib of 30 mg is administered as two 15 mg dosage forms.

[0025] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when a daily dose of 15 mg of upadacitinib is administered during the period when the patient is receiving a strong CYP3A4 inhibitor.

[0026] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0027] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0028] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient is administered a strong CYP3A4 inhibitor. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0029] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0030] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib is reduced from 45 mg to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0031] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0032] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient receiving a strong CYP3A4 inhibitor, comprising: Determine the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor and select from 45 mg, 30 mg, or 15 mg; assessing whether the patient is receiving a strong CYP3A4 inhibitor; administering a reduced daily dose of 30 mg upadacitinib to patients receiving a strong CYP3A4 inhibitor, followed by a daily dose of 45 mg upadacitinib for the period the patient is receiving a strong CYP3A4 inhibitor; administering a reduced daily dose of 15 mg upadacitinib to patients receiving a strong CYP3A4 inhibitor, followed by a daily dose of 30 mg upadacitinib for the period the patient is receiving a strong CYP3A4 inhibitor; and administering an upadacitinib dose of 15 mg per day to a patient receiving a strong CYP3A4 inhibitor, and maintaining the upadacitinib dose at 15 mg per day for the period the patient is receiving a strong CYP3A4 inhibitor; The present invention provides a method comprising:

[0033] In one aspect, the disclosure provides a method of treating a patient receiving a strong CYP3A4 inhibitor concomitantly with upadacitinib, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; Reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while the patient is receiving a strong CYP3A4 inhibitor; or Maintaining the recommended daily upadacitinib dose of 15 mg while patients are receiving a strong CYP3A4 inhibitor The present invention provides a method comprising:

[0034] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient receiving a strong CYP3A4 inhibitor, comprising: Determine the recommended daily dose of upadacitinib when the patient is not receiving a strong CYP3A4 inhibitor and select from 45 mg, 30 mg, or 15 mg; Assessing whether the patient is receiving a strong CYP3A4 inhibitor; (a) reducing the recommended daily upadacitinib dose of 45 mg to a daily dose of 30 mg upadacitinib while the patient is receiving a strong CYP3A4 inhibitor; (b) reducing the recommended daily upadacitinib dose of 30 mg to a daily dose of 15 mg upadacitinib while the patient is receiving a strong CYP3A4 inhibitor; or (c) maintaining the recommended daily upadacitinib dose at 15 mg while the patient is receiving a strong CYP3A4 inhibitor The present invention provides a method comprising:

[0035] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient receiving a strong CYP3A4 inhibitor, comprising: Determine the recommended daily dose of upadacitinib when the patient is not receiving a strong CYP3A4 inhibitor and select from 45 mg, 30 mg, or 15 mg; Assessing whether the patient is receiving a strong CYP3A4 inhibitor; (a) if the patient is receiving a strong CYP3A4 inhibitor and a daily dose of 45 mg of upadacitinib, administering a daily dose of 30 mg of upadacitinib for the period during which the patient is receiving the strong CYP3A4 inhibitor; (b) if the patient is receiving a strong CYP3A4 inhibitor and a daily dose of 30 mg of upadacitinib, administering a daily dose of 15 mg of upadacitinib for the period during which the patient is receiving the strong CYP3A4 inhibitor; or (c) if the patient is receiving a strong CYP3A4 inhibitor and a 15 mg daily dose of upadacitinib, administering a 15 mg daily dose of upadacitinib for the period during which the patient is receiving the strong CYP3A4 inhibitor. The present invention provides a method comprising:

[0036] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib of 30 mg is administered without caution during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the daily dose of upadacitinib of 30 mg is administered during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib of 30 mg is administered as two 15 mg dosage forms.

[0037] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when a daily dose of 15 mg of upadacitinib is administered during the period when the patient is receiving a strong CYP3A4 inhibitor.

[0038] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0039] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0040] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient is administered a strong CYP3A4 inhibitor. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0041] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0042] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0043] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0044] In a further aspect, the disclosure provides a method of treating a patient with severe renal impairment with upadacitinib, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0045] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0046] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0047] In another aspect, the disclosure provides a method for improving safety in treating a disease for which treatment with upadacitinib is clinically approved in patients with severe renal impairment, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0048] In a further aspect, the disclosure provides a method of reducing the occurrence or likelihood of an adverse event in treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0049] In yet another aspect, the disclosure provides a method of treating an FDA approved indication with upadacitinib in patients with severe renal impairment, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0050] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient has severe renal impairment. In some embodiments, a daily dose of 30 mg of upadacitinib is administered without caution during the period when the patient has severe renal impairment. In some embodiments, when a daily dose of 30 mg of upadacitinib is administered during the period when the patient has severe renal impairment, the patient is closely monitored for adverse reactions. In some embodiments, a daily dose of 30 mg of upadacitinib is administered as two 15 mg dosage forms.

[0051] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient has severe renal impairment. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient has severe renal impairment. In some embodiments, when a daily dose of 15 mg of upadacitinib is administered during the period when the patient has severe renal impairment, the patient is closely monitored for adverse reactions.

[0052] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 15 mg, and that dose is maintained for the duration of time that the patient has severe renal impairment. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution for the duration of time that the patient has severe renal impairment. In some embodiments, when a daily dose of 15 mg of upadacitinib is administered for the duration of time that the patient has severe renal impairment, the patient is closely monitored for adverse reactions.

[0053] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 15 mg, and that dose is maintained for the duration of time that the patient has severe renal impairment. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution for the duration of time that the patient has severe renal impairment. In some embodiments, when a daily dose of 15 mg of upadacitinib is administered for the duration of time that the patient has severe renal impairment, the patient is closely monitored for adverse reactions.

[0054] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient has severe renal impairment. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0055] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0056] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0057] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0058] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: Determine the recommended daily dose of upadacitinib for patients without severe renal impairment and select from 45 mg, 30 mg, or 15 mg; Reducing the recommended daily upadacitinib dose from 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily dose of upadacitinib from 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0059] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: assessing whether the patient has severe renal impairment; Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0060] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: Reducing the recommended daily upadacitinib dose for patients with renal impairment from 45 mg to a daily upadacitinib dose of 30 mg for as long as the patient has severe renal impairment; reducing the recommended daily upadacitinib dose for patients with renal impairment from 30 mg to a daily upadacitinib dose of 15 mg for the duration of the patient's severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0061] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: Determine the recommended daily dose of upadacitinib for patients without severe renal impairment and select from 45 mg, 30 mg, or 15 mg; assessing whether the patient has severe renal impairment; Reducing the recommended daily upadacitinib dose from 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily dose of upadacitinib from 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0062] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient has severe hepatic impairment. In some embodiments, the daily dose of upadacitinib of 30 mg is administered without caution during the period when the patient has severe hepatic impairment. In some embodiments, when the daily dose of upadacitinib of 30 mg is administered during the period when the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions. In some embodiments, the daily dose of upadacitinib of 30 mg is administered as two 15 mg dosage forms.

[0063] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient has severe hepatic impairment. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient has severe hepatic impairment. In some embodiments, when a daily dose of 15 mg of upadacitinib is administered during the period when the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions.

[0064] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 15 mg, and the dose is maintained for the duration of time that the patient has severe hepatic impairment. In some embodiments, the daily dose of upadacitinib is administered without caution for the duration of time that the patient has severe hepatic impairment. In some embodiments, when the daily dose of upadacitinib is administered for the duration of time that the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions.

[0065] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 15 mg, and the dose is maintained for the duration of time that the patient has severe hepatic impairment. In some embodiments, the daily dose of upadacitinib is administered without caution for the duration of time that the patient has severe hepatic impairment. In some embodiments, when the daily dose of upadacitinib is administered for the duration of time that the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions.

[0066] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient has severe liver dysfunction. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0067] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0068] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0069] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0070] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: Determine the recommended daily dose of upadacitinib for patients without severe renal impairment and select from 45 mg, 30 mg, or 15 mg; assessing whether the patient has severe renal impairment; administering a daily dose of 30 mg of upadacitinib to a patient with severe renal impairment for as long as the patient has severe renal impairment; and administering a 15 mg daily dose of upadacitinib to a patient with severe renal impairment for as long as the patient has severe renal impairment. The present invention provides a method comprising:

[0071] In a further aspect, the disclosure provides a method of treating a patient with severe renal impairment with upadacitinib, comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while the patient has severe renal impairment; reducing the recommended daily upadacitinib dose of 30 mg to 15 mg for the duration of time the patient has severe renal impairment; and Maintain the patient on the recommended daily upadacitinib dose of 15 mg for the duration of their severe renal impairment. The present invention provides a method comprising:

[0072] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: determining the recommended daily dose of upadacitinib and selecting from 45 mg, 30 mg, or 15 mg when the patient does not have severe renal impairment; assessing whether the patient has severe renal impairment; (a) reducing the recommended daily upadacitinib dose of 45 mg to a daily dose of 30 mg upadacitinib for the duration of the patient's severe renal impairment; (b) reducing the recommended daily dose of 30 mg of upadacitinib to a daily dose of 15 mg of upadacitinib for the duration of the patient's severe renal impairment; or (c) maintaining the patient at the recommended daily dose of 15 mg of upadacitinib for the duration of the patient's severe renal impairment. The present invention provides a method comprising:

[0073] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in a patient with severe renal impairment, comprising: determining the recommended daily dose of upadacitinib and selecting from 45 mg, 30 mg, or 15 mg when the patient does not have severe renal impairment; assessing whether the patient has severe renal impairment; (a) if the patient has severe renal impairment and is receiving a daily dose of 45 mg of upadacitinib, administering a daily dose of 30 mg of upadacitinib for the duration of time the patient has severe renal impairment; (b) if the patient has severe renal impairment and is receiving a daily dose of 30 mg of upadacitinib, administering a daily dose of 15 mg of upadacitinib for the duration of time the patient has severe renal impairment; or (c) if the patient has severe renal impairment and is receiving a daily dose of 15 mg of upadacitinib, administering a daily dose of 15 mg of upadacitinib for as long as the patient has severe renal impairment. The present invention provides a method comprising:

[0074] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient has severe hepatic impairment. In some embodiments, the daily dose of upadacitinib of 30 mg is administered without caution during the period when the patient has severe hepatic impairment. In some embodiments, when the daily dose of upadacitinib of 30 mg is administered during the period when the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions. In some embodiments, the daily dose of upadacitinib of 30 mg is administered as two 15 mg dosage forms.

[0075] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient has severe hepatic impairment. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient has severe hepatic impairment. In some embodiments, when a daily dose of 15 mg of upadacitinib is administered during the period when the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions.

[0076] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 15 mg, and the dose is maintained for the duration of time that the patient has severe hepatic impairment. In some embodiments, the daily dose of upadacitinib is administered without caution for the duration of time that the patient has severe hepatic impairment. In some embodiments, when the daily dose of upadacitinib is administered for the duration of time that the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions.

[0077] In some embodiments, the daily dose of upadacitinib for patients without severe renal impairment is 15 mg, and the dose is maintained for the duration of time that the patient has severe hepatic impairment. In some embodiments, the daily dose of upadacitinib is administered without caution for the duration of time that the patient has severe hepatic impairment. In some embodiments, when the daily dose of upadacitinib is administered for the duration of time that the patient has severe hepatic impairment, the patient is closely monitored for adverse reactions.

[0078] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient has severe liver dysfunction. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0079] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0080] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0081] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0082] In a further aspect, the disclosure provides a method of treating an adult patient 65 years of age or older with upadacitinib, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0083] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in an adult patient 65 years of age or older, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0084] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in an adult patient 65 years of age or older, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0085] In another aspect, the disclosure provides a method for improving safety in treating a disease for which upadacitinib is clinically approved for treatment in adult patients 65 years of age or older, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0086] In a further aspect, the disclosure provides a method of reducing the occurrence or likelihood of an adverse event in treating a disease for which upadacitinib is clinically approved for treatment in an adult patient 65 years of age or older, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0087] In yet another aspect, the disclosure provides a method of treating an FDA approved indication with upadacitinib in an adult patient 65 years of age or older, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0088] In some embodiments, the daily dose of upadacitinib for adult patients not 65 years of age or older is 45 mg and is maintained at that dose. In some embodiments, in adult patients 65 years of age or older, a daily dose of 45 mg of upadacitinib is administered without caution. In some embodiments, when a daily dose of 45 mg of upadacitinib is administered, the patient is closely monitored for adverse reactions. In some embodiments, a daily dose of 45 mg of upadacitinib is administered as three 15 mg dosage forms.

[0089] In some embodiments, the daily dose of upadacitinib for adult patients not aged 65 or older is 30 mg, which is reduced to a daily dose of 15 mg upadacitinib. In some embodiments, the daily dose of 15 mg upadacitinib is administered without caution. In some embodiments, when administering a daily dose of 15 mg upadacitinib, patients are closely monitored for adverse reactions.

[0090] In some embodiments, the daily dose of upadacitinib for patients not aged 65 or older is 15 mg and is maintained at that dose. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution. In some embodiments, patients are closely monitored for adverse reactions when administering a daily dose of 15 mg of upadacitinib.

[0091] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0092] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0093] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of 45 mg of upadacitinib is maintained at 45 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of 30 mg of upadacitinib can be considered for patients with refractory disease, severe disease, or widespread disease.

[0094] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0095] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in an adult patient 65 years of age or older, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0096] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in an adult patient 65 years of age or older, comprising: assessing whether the patient is 65 years of age or older; Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0097] In one aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in an adult patient 65 years of age or older, comprising: determining a recommended daily dose of upadacitinib for patients not 65 years of age or older and selecting from 45 mg, 30 mg, or 15 mg; assessing whether the patient is 65 years of age or older; Maintain the recommended daily dose of upadacitinib at 45 mg; and reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; and and maintaining the recommended daily dose of upadacitinib at 15 mg. The present invention provides a method comprising:

[0098] In some embodiments, the daily dose of upadacitinib for adult patients not aged 65 or older is 30 mg, which is reduced to a daily dose of 15 mg upadacitinib. In some embodiments, the daily dose of 15 mg upadacitinib is administered without caution. In some embodiments, when administering a daily dose of 15 mg upadacitinib, patients are closely monitored for adverse reactions.

[0099] In some embodiments, the daily dose of upadacitinib for patients not aged 65 or older is 15 mg and is maintained at that dose. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution. In some embodiments, patients are closely monitored for adverse reactions when administering a daily dose of 15 mg of upadacitinib.

[0100] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0101] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0102] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0103] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0104] In a further aspect, the disclosure provides a method of treating an adult patient 65 years of age or older, comprising: Maintain the recommended daily dose of upadacitinib at 45 mg; Reducing the recommended daily upadacitinib dose of 30 mg to 15 mg; or Steps to maintain the recommended daily dose of upadacitinib at 15 mg The present invention provides a method comprising:

[0105] In another aspect, the disclosure provides a method for treating a disease for which treatment with upadacitinib is clinically approved in an adult patient 65 years of age or older, comprising: When the patient is not an adult patient 65 years of age or older, determining the recommended daily dose of upadacitinib and selecting from 45 mg, 30 mg, or 15 mg; assessing whether the patient is an adult patient 65 years of age or older; (a) maintaining the recommended daily dose of upadacitinib at 45 mg; (b) reducing the recommended daily dose of upadacitinib from 30 mg to 15 mg; or (c) maintaining the recommended daily dose of 15 mg of upadacitinib The present invention provides a method comprising:

[0106] In some embodiments, the daily dose of upadacitinib for adult patients not aged 65 or older is 45 mg, and the dose is maintained at 45 mg. In some embodiments, a daily dose of 45 mg of upadacitinib is administered without caution. In some embodiments, when a daily dose of 45 mg of upadacitinib is administered, patients are closely monitored for adverse reactions. In some embodiments, a daily dose of 45 mg of upadacitinib is administered as three 15 mg dosage forms.

[0107] In some embodiments, the daily dose of upadacitinib for adult patients not aged 65 or older is 30 mg, which is reduced to a daily dose of 15 mg upadacitinib. In some embodiments, the daily dose of 15 mg upadacitinib is administered without caution. In some embodiments, when administering a daily dose of 15 mg upadacitinib, patients are closely monitored for adverse reactions.

[0108] In some embodiments, the daily dose of upadacitinib for adult patients not aged 65 or older is 15 mg and is maintained at that dose. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution. In some embodiments, patients are closely monitored for adverse reactions when administering a daily dose of 15 mg of upadacitinib.

[0109] In some embodiments, the daily dose of upadacitinib for adult patients not aged 65 or older is 15 mg and is maintained at that dose. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution. In some embodiments, patients are closely monitored for adverse reactions when administering a daily dose of 15 mg of upadacitinib.

[0110] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0111] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0112] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0113] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0114] In a further aspect, a method of administering upadacitinib to a patient in need thereof, wherein the patient has been administered a strong CYP3A4 inhibitor for a period of time, the method comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; Reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while the patient is receiving a strong CYP3A4 inhibitor; or Administer the recommended daily dose of 15 mg upadacitinib regardless of whether or not the patient is receiving a strong CYP3A4 inhibitor. The present invention provides a method comprising:

[0115] In some embodiments, the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, a daily dose of 30 mg of upadacitinib is administered without caution during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, when a daily dose of 30 mg of upadacitinib is administered during the period when the patient receives a strong CYP3A4 inhibitor, the patient is closely monitored for adverse reactions. In some embodiments, a daily dose of 30 mg of upadacitinib is administered as two 15 mg dosage forms.

[0116] In some embodiments, the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when a daily dose of 15 mg of upadacitinib is administered during the period when the patient is receiving a strong CYP3A4 inhibitor.

[0117] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0118] In some embodiments, the daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when the 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0119] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient is administered a strong CYP3A4 inhibitor. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0120] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0121] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0122] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0123] In a further aspect, there is provided a method of administering a strong CYP3A4 inhibitor to a patient in need thereof for a period of time, wherein the patient is administered upadacitinib; Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; Reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while the patient is receiving a strong CYP3A4 inhibitor; or Administer the recommended daily dose of 15 mg upadacitinib regardless of whether or not the patient is receiving a strong CYP3A4 inhibitor. The present invention provides a method comprising:

[0124] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease.

[0125] In a further aspect, a method of administering upadacitinib to a patient in need thereof, wherein the patient has been administered a strong CYP3A4 inhibitor for a period of time, the method comprising: Reducing the recommended daily upadacitinib dose of 45 mg to 30 mg while patients are receiving a strong CYP3A4 inhibitor; Reducing the recommended daily upadacitinib dose of 30 mg to 15 mg while the patient is receiving a strong CYP3A4 inhibitor; or Administer the recommended daily dose of 15 mg upadacitinib regardless of whether or not the patient is receiving a strong CYP3A4 inhibitor. The present invention provides a method comprising:

[0126] In some embodiments, the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 45 mg, and the daily dose of upadacitinib is reduced to 30 mg during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, a daily dose of 30 mg of upadacitinib is administered without caution during the period when the patient receives a strong CYP3A4 inhibitor. In some embodiments, when a daily dose of 30 mg of upadacitinib is administered during the period when the patient receives a strong CYP3A4 inhibitor, the patient is closely monitored for adverse reactions. In some embodiments, a daily dose of 30 mg of upadacitinib is administered as two 15 mg dosage forms.

[0127] In some embodiments, the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 30 mg, and the daily dose of upadacitinib is reduced to 15 mg during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, a daily dose of 15 mg of upadacitinib is administered without caution during the period when the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when a daily dose of 15 mg of upadacitinib is administered during the period when the patient is receiving a strong CYP3A4 inhibitor.

[0128] In some embodiments, the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, a 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when a 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0129] In some embodiments, the recommended daily dose of upadacitinib for patients not receiving a strong CYP3A4 inhibitor is 15 mg, and that dose is maintained for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, a 15 mg daily dose of upadacitinib is administered without caution for the duration that the patient is receiving a strong CYP3A4 inhibitor. In some embodiments, the patient is closely monitored for adverse reactions when a 15 mg daily dose of upadacitinib is administered for the duration that the patient is receiving a strong CYP3A4 inhibitor.

[0130] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is rheumatoid arthritis, and a daily dose of 15 mg of upadacitinib is maintained. In some embodiments, the patient is a rheumatoid arthritis patient, and a daily dose of 15 mg of upadacitinib is administered without caution during the period in which the patient is administered a strong CYP3A4 inhibitor. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is psoriatic arthritis, and a daily dose of 15 mg of upadacitinib is maintained.

[0131] In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is maintained at 15 mg. In some embodiments, the disease for which upadacitinib is clinically approved for treatment is atopic dermatitis, and the daily dose of upadacitinib is reduced from 30 mg to 15 mg.

[0132] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is ulcerative colitis, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory, severe, or widespread disease.

[0133] In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and the daily dose of upadacitinib of 45 mg is reduced to 30 mg. In some embodiments, the disease for which treatment with upadacitinib is clinically approved is Crohn's disease, and a daily dose of upadacitinib of 30 mg can be considered for patients with refractory disease, severe disease, or widespread disease. [Brief description of the drawings]

[0134] [Figure 1] FIG. 1 is a graph showing the proportion of patients achieving American College of Rheumatology score of ≧20% improvement in rheumatoid arthritis (ACR20) when treated with upadacitinib 15 mg + methotrexate or methotrexate alone. [Diagram 2]FIG. 1 is a graph showing the proportion of patients achieving American College of Rheumatology ≥ 20% improvement in psoriatic arthritis (ACR20) when treated with upadacitinib 15 mg or administered placebo. [Diagram 3] FIG. 1 shows the proportion of patients with atopic dermatitis achieving a 4-point improvement in the Worst Pruritus NRS when treated with upadacitinib 15 mg, 30 mg, or administered placebo in the AD-1 study. [Figure 4] FIG. 1 shows the proportion of patients with atopic dermatitis achieving a 4-point improvement in the worst pruritus NRS when treated with upadacitinib 15 mg + topical corticosteroid (TCS), upadacitinib 30 mg + TCS, or placebo + TCS. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0135] The present specification uses examples to disclose the present invention and to enable any person skilled in the art to make and use any of the disclosed compositions, and to perform any of the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have no elements different from the literal language of the claims, or if they contain elements equivalent to those of the claims.

[0136] definition The section headings used in this section, and throughout this disclosure, are not intended to be limiting.

[0137] Where numerical ranges are recited, each intervening number within the range is expressly contemplated with the same degree of precision. For example, in the range 6 to 9, 7 and 8 are contemplated in addition to 6 and 9, and in the range 6.0 to 7.0, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0 are expressly contemplated. Similarly, all recited ratios include all sub-ratios within the broader ratio.

[0138] The singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0139] The term "about" generally refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" can include numbers that are rounded to the nearest significant figure.

[0140] Unless otherwise required by context, the terms "comprise," "comprises," and "comprising" are used with the basic and clear understanding that they are to be interpreted inclusively, not exclusively, and that Applicant intends each word to be so interpreted in describing this patent, including the claims that follow.

[0141] The term "AUC" refers to the area under the curve. AUC is the definite integral of the curve that represents the variation of drug concentration in plasma as a function of time.

[0142] The term “C max " refers to the total amount of T, expressed herein as ng / mL, resulting from oral ingestion of a single dose or the indicated number of doses of a dosage form or pharmaceutical composition, such as the dosage forms and compositions of the present disclosure. max Unless otherwise specified, max refers to the overall maximum observed concentration.

[0143] As used herein, the term "daily dose of upadacitinib" refers to a dose administered once a day to a patient in extended release form. The recommended daily dose of upadacitinib may vary as disclosed herein and may be 15 mg, 30 mg, or 45 mg. For the avoidance of doubt, the 45 mg and 30 mg doses are intended to encompass multiples of 15 mg (e.g., 3 x 15 mg or 2 x 15 mg doses), administered together or sequentially and separated by a period of time.

[0144] As used herein, the terms "treat", "treatment" and "therapy" are meant to include therapeutic measures as well as preventative or suppressive measures for a disease or disorder that produce any clinically desirable or beneficial effect, including, but not limited to, alleviation or mitigation of one or more symptoms, regression, slowing or halting of progression of a disease or disorder. Thus, for example, the term treatment includes administering an agent before or after the onset of symptoms of a disease or disorder, thereby preventing or eliminating one or more signs of a disease or disorder. As another example, the term includes administering an agent after clinical manifestation of a disease to combat the symptoms of a disease. Furthermore, administration of an agent after onset and after clinical manifestation includes "treatment" or "therapy" as used herein, when administration affects clinical parameters of a disease or disorder, such as the degree of tissue damage or the amount or extent of metastasis, regardless of whether the treatment leads to improvement of the disease. Furthermore, so long as the compositions of the present disclosure, alone or in combination with another therapeutic agent, reduce or ameliorate at least one symptom of the disorder being treated compared to that symptom in the absence of the JAK1 inhibitor composition, the result shall be considered an effective treatment of the underlying disorder, regardless of whether all symptoms of the disorder are alleviated.

[0145] Recommended upadacitinib dosing In some embodiments, the methods disclosed herein include determining a recommended daily dose of upadacitinib. The recommended dose of upadacitinib may vary depending on many factors, including, but not limited to, the particular disease being treated, induction phase versus maintenance phase, age of the patient, comorbidities, and concurrent use of certain drug therapies as described below in this specification. Unless otherwise indicated, the recommended dose is the daily dose recommended in the absence of comorbid factors (i.e., renal or hepatic impairment, or concurrent administration of drugs that interact with the metabolism of upadacitinib).

[0146] In some embodiments, the methods disclosed herein include determining a recommended daily dose of upadacitinib in patients who are not receiving a strong CYP3A4 inhibitor or who do not have severe renal impairment, hi some embodiments, the daily dose in patients who are not receiving a strong CYP3A4 inhibitor or who do not have severe renal impairment is 45 mg, 30 mg, or 15 mg.

[0147] The recommended upadacitinib dose for patients with rheumatoid arthritis is 15 mg taken once daily.

[0148] The recommended upadacitinib dose for patients with psoriatic arthritis is 15 mg taken once daily.

[0149] The recommended dose of upadacitinib in patients with atopic dermatitis may vary depending on age and / or response to treatment, and is generally the lowest effective dose required to maintain a response. The recommended dose of upadacitinib in pediatric patients aged 12 years or older weighing at least 40 kg is 15 mg once daily to initiate treatment. If there is no adequate response, the physician may consider increasing the dose to 30 mg once daily. If there is no adequate response at the 30 mg dose, treatment should be interrupted. The recommended dose of upadacitinib in adult patients under 65 years old is 15 mg once daily to initiate treatment. If there is no adequate response at the 30 mg dose, the physician may consider increasing the dose to 30 mg once daily. In some embodiments, the dose is a single 30 mg dosage form. In some embodiments, the dose is administered as two 15 mg dosage forms. If there is no adequate response at the 30 mg dose, treatment should be interrupted. The recommended upadacitinib dose in adult patients 65 years of age and older is 15 mg taken once daily.

[0150] The recommended dose of upadacitinib in patients with ulcerative colitis is an induction dose of 45 mg once daily for 8 weeks. In some embodiments, the dose is a single 45 mg dosage form. In some embodiments, the dose is administered as three 15 mg dosage forms. The recommended maintenance dose of upadacitinib in patients with ulcerative colitis is 15 mg once daily. A maintenance dose of 30 mg once daily can be considered for patients with refractory, severe, or widespread disease. In some embodiments, the dose is a single 30 mg dosage form. In some embodiments, the dose is administered as two 15 mg dosage forms. If the 30 mg dose does not result in an adequate response, treatment should be discontinued. The lowest effective dose required to maintain a response should be used.

[0151] The recommended dosage in patients with renal or hepatic impairment may differ from the recommended dosage in the absence of renal or hepatic impairment, as further described herein below. Modifications to the recommended dosage may be necessary due to drug interactions, as further described herein below.

[0152] Upadacitinib Metabolism The potential of upadacitinib to act as an effector in drug-drug interactions was thoroughly investigated in vitro. In vitro, upadacitinib was a substrate for CYP3A4, CYP2D6, P-pg, and BCRP. Upadacitinib was primarily metabolized by CYP3A4 and less by CYP2D6. Upadacitinib was not a substrate for CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2J2, FMO1, FMO3, OATP1B1, OATP1B3, or OCT1 in vitro. Upadacitinib was an inducer of CYP3A4 and CYP2B6 in vitro, and results for CYP1A2 were borderline with only slight concentration-dependent.

[0153] In vivo, the contribution of CYP2D6 is expected to show minor comparability of upadacitinib CL / F in extensive and poor metabolizers in Phase 1 and Phase 2 populations (popPK analysis). Given the comparability of upadacitinib CL / F between extensive and poor metabolizers of YP2D6, concomitant medications that are strong inhibitors of CYP2D6 are not expected to affect upadacitinib plasma exposure.

[0154] There was no in vivo relevant inhibition by upadacitinib of any of the enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4) or transporters (P-gp, BCRP, BSEP, OATP1B1, OATB1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2K) evaluated in vitro.

[0155] Upadacitinib elimination pathway Upadacitinib is excreted via the renal and hepatic routes. 14 Following administration of a single dose of [C]-radiolabelled upadacitinib immediate-release solution, upadacitinib was primarily excreted in the urine (24%) and feces (31%) as unchanged parent substance. This fraction could originate from either absorbed and biliarily secreted upadacitinib or unabsorbed drug.

[0156] Renal clearance indicates some contribution of renal transporters to excretion; however, renal secretion is estimated to contribute no more than 25% of excretion. The effect of renal impairment on the PK of upadacitinib was evaluated in a Phase 1 study (n=6, mild renal impairment; n=6, moderate renal impairment; n=6, severe renal impairment; n=6, normal renal function). Results from this study showed that upadacitinib exposure (AUC infIt was demonstrated that the median values ​​of CL / F and Vc / F were 18%, 33%, and 44% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. This is consistent with the renal pathway contributing approximately 25% to the elimination of upadacitinib. As used herein, reference to "severe renal impairment" means a creatinine clearance of less than 30 mL / min. In population pharmacokinetic analyses, age was evaluated as a continuous covariate as well as a discrete covariate (adolescents [body weight ≧40 kg] vs. adults) with respect to upadacitinib clearance (CL / F) and volume of distribution (Vc / F) and was not found to be statistically significant.

[0157] In studies of subjects with mild hepatic impairment (Child-Pugh classification [CP]-A, N=6), moderate hepatic impairment (CP-B, N=6), and normal hepatic function (N=6), the effect of mild and moderate hepatic impairment on the pharmacokinetics of upadacitinib was moderate. The AUC of upadacitinib was increased by 28% and 24%, respectively, in subjects with mild and moderate hepatic impairment compared to normal subjects.

[0158] The influence of various intrinsic factors has been evaluated in dedicated PK studies in renal impairment, hepatic impairment and Asian subjects, as well as in population pharmacokinetic analyses derived from Phase 2 / 3 studies. Population pharmacokinetic analyses showed no relevant effects of sex, race, age or weight on the pharmacokinetic parameters of upadacitinib. Data in patients aged 75 years and older are limited, and there are no pharmacokinetic data in children and adolescents.

[0159] Upadacitinib-Potential Drug Interactions The effect of multiple doses of upadacitinib 30 mg on the pharmacokinetics of specific substrates of different CYP enzymes (CYP1A2, 3A, 2D6, 2C9, and 2C19) was evaluated in an in vivo cocktail study, and potential drug-drug interactions between upadacitinib and commonly used concomitant medicinal products, as well as probe substrates of CYP450 enzymes, were characterized in several Phase 1 studies.

[0160] In vivo, upadacitinib (at a dose of 30 mg) has been shown to be a weak inducer of PXR-mediated metabolism by CYP3A4 after a 26% reduction in oral midazolam, a sensitive CYP3A4 substrate, an effect that would be predicted to be lower at the clinical dose of 15 mg.

[0161] The effect of ketoconazole 400 mg QD, a strong CYP3A / P-gp inhibitor, on upadacitinib 30 mg QD in the IR formulation was weak to moderate; upadacitinib AUC and Cmax were increased by 1.8-fold and 1.7-fold, respectively, compared to upadacitinib administered alone. There was no effect on half-life, indicating an effect primarily on presystemic metabolism or P-gp. The effect of moderate CYP3A4 / P-gp inhibitors on upadacitinib exposure is not expected to be clinically relevant.

[0162] Following multiple dosing of rifampicin 600 mg QD for 8 days, a strong CYP3A / P-gp inducer, upadacitinib AUC and Cmax were decreased by 60% and 50%, respectively. In summary, strong inducers of CYP3A (e.g., rifampin) reduce upadacitinib plasma exposure by approximately half. Strong CYP3A inhibitors (e.g., ketoconazole) increase upadacitinib AUC by 75% and maximum observed concentration (Cmax) by 70%.

[0163] Further results from these studies are summarized as follows: Following coadministration with methotrexate, there was no effect on the exposure of upadacitinib. Upadacitinib 30 mg QD decreased the AUC of rosuvastatin by 33% and atorvastatin by 23%; the AUC of its metabolite ortho-hydroxyatorvastatin remained unchanged. Following multiple doses of upadacitinib ER 30 mg, there was no inducing effect of upadacitinib on ethinyl estradiol / levonorgestrel. There were no relevant effects on the AUC or Cmax of bupropion, therefore upadacitinib was not shown to be an inducer of CYP2B6 in vivo. There were no effects related to plasma exposure of other PXR-regulated enzymes (CYP2C9 and 2C19) or enzymes regulated by the Ah-receptor (CYP1A2). Upadacitinib has no clinically relevant effects on the plasma exposure of MTX, ethinyl estradiol, levonorgestrel, statins, or drugs that are substrates metabolized by CYP1A2, CYP2B6, CYP2D6, CYP2C19, CYP2C9, or CYP3A. Concomitant administration of strong CYP2D6 inhibitors, OATP1B inhibitors, MTX, pH-adjusting medications, or statins has no effect on the plasma exposure of upadacitinib. Overall, plasma exposure was similar between adult and adolescent subjects in atopic dermatitis studies with upadacitinib.

[0164] As described hereinabove, a strong CYP3A4 inhibitor (e.g., ketoconazole) increases upadacitinib AUC by 75% and increases maximum observed concentration (Cmax) by 70%. As used herein, the term "strong CYP3A4 inhibitor" refers to a drug that increases the AUC of a sensitive CYP3A4 substrate (e.g., midazolam) by an amount of ≧5-fold. Examples of classes of drugs that contain strong CYP3A4 inhibitors include certain antibiotics, antifungals, antidepressants, and antivirals. Examples of antibiotics that are strong CYP3A4 inhibitors include, but are not limited to, clarithromycin, telithromycin, and troleandomycin. Examples of antifungals that are strong CYP3A4 inhibitors include, but are not limited to, itraconazole, ketoconazole, posaconazole, and voriconazole. Examples of antiviral drugs that are strong CYP3A4 inhibitors include, but are not limited to, the class of protease inhibitors, including atazanavir, boceprevir, cobicistat, danoprevir, darunavir, dasabuvir, elvitegravir, indinavir, lopinavir, nelfinavir, ombitasvir, paritaprevir, ritonavir, saquinavir, telaprevir, and ipranavir.An example of an antidepressant that is a strong inhibitor of CYP3A4 is nefazodone.Grapefruit juice can be a strong CYP3A4 inhibitor, depending on the source and preparation.

[0165] Upadacitinib Dosing Adjustments Due to Drug Interactions In some embodiments, the methods disclosed herein include a step of assessing whether the patient is receiving a strong CYP3A4 inhibitor. When both upadacitinib and a strong CYP3A4 inhibitor are administered to a patient, the recommended dosage of upadacitinib may differ from the recommended dosage of upadacitinib in patients without severe renal impairment. Dosage adjustments depend on the disease treated by upadacitinib and the dose recommended for treating the particular disease in the absence of a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib in patients receiving a strong CYP3A4 inhibitor is reduced compared to the daily dose of upadacitinib in the absence of a strong CYP3A4 inhibitor. In some embodiments, the daily dose of upadacitinib in patients receiving a strong CYP3A4 inhibitor is maintained compared to the daily dose of upadacitinib in the absence of a strong CYP3A4 inhibitor (i.e., no dosage adjustment is required). Thus, in some embodiments, the methods disclosed herein comprise reducing or maintaining the dose of upadacitinib. In some embodiments, the methods disclosed herein comprise reducing the recommended daily dose of upadacitinib from 45 mg to 30 mg, or from 30 mg to 15 mg, in a patient receiving a strong CYP3A4 inhibitor. In some embodiments, the methods disclosed herein comprise maintaining the recommended daily dose of upadacitinib at 15 mg in a patient receiving a strong CYP3A4 inhibitor.

[0166] For patients receiving upadacitinib for the treatment of rheumatoid arthritis or psoriatic arthritis who are not receiving a strong CYP3A4 inhibitor, the recommended daily dose is 15 mg.For patients receiving upadacitinib for the treatment of rheumatoid arthritis or psoriatic arthritis who are receiving a strong CYP3A4 inhibitor, the recommended dose is 15 mg once daily.

[0167] In some embodiments, for patients receiving upadacitinib for the treatment of atopic dermatitis, if a strong CYP3A4 inhibitor is not administered, the recommended daily dose is 15 mg once daily. For patients receiving upadacitinib for the treatment of atopic dermatitis, if a strong CYP3A4 inhibitor is administered, the recommended dose is 15 mg once daily. Thus, in some embodiments, the methods disclosed herein include maintaining a recommended daily dose of upadacitinib at 15 mg.

[0168] In some embodiments, for patients receiving upadacitinib for the treatment of atopic dermatitis, if a strong CYP3A4 inhibitor is not administered, the recommended daily dose is 30 mg once daily. For patients receiving upadacitinib for the treatment of atopic dermatitis, if a strong CYP3A4 inhibitor is administered, the recommended dose is 15 mg once daily. Thus, in some embodiments, the methods disclosed herein include reducing the recommended daily dose of upadacitinib from 30 mg to 15 mg.

[0169] For patients receiving upadacitinib for the treatment of ulcerative colitis who are not receiving a strong CYP3A4 inhibitor, the recommended daily dose is an induction dose of 45 mg once daily for 8 weeks, followed by a maintenance dose of 15 mg once daily, or for patients with refractory, severe, or extensive disease, 30 mg once daily. For patients receiving upadacitinib for the treatment of ulcerative colitis who are receiving a strong CYP3A4 inhibitor, the recommended dose is 30 mg once daily for induction and 15 mg once daily for maintenance. Thus, in some embodiments, the methods disclosed herein include reducing the recommended daily induction dose of upadacitinib from 45 mg to 30 mg. Thus, in some embodiments, the methods disclosed herein include reducing the recommended daily maintenance dose of upadacitinib from 30 mg to 15 mg. In some embodiments, the methods disclosed herein comprise maintaining a recommended daily maintenance dose of 15 mg of upadacitinib.

[0170] In some embodiments, the daily dose of 30 mg is maintained and the dose of 30 mg is administered without caution, in some embodiments, the reduced daily dose of 30 mg is administered without caution.

[0171] In some embodiments, the daily dose of 30 mg is maintained and the patient is closely monitored for adverse reactions. In some embodiments, a reduced daily dose of 30 mg is administered and the patient is closely monitored for adverse reactions.

[0172] In some embodiments, the daily dose of 15 mg is maintained and the dose of 15 mg is administered without caution, in some embodiments, the reduced daily dose of 15 mg is administered without caution.

[0173] In some embodiments, the daily dose of 15 mg is maintained and the patient is closely monitored for adverse reactions. In some embodiments, a reduced daily dose of 15 mg is administered and the patient is closely monitored for adverse reactions.

[0174] In any of the above embodiments, it is contemplated herein that the 30 mg dose may be administered as two 15 mg dosage forms.

[0175] Upadacitinib Dosing in Patients with Renal Impairment In some embodiments, the methods disclosed herein include assessing whether the patient has renal impairment. When upadacitinib is administered to a patient with renal impairment, the recommended dose of upadacitinib may differ from the recommended dose in the absence of renal impairment. Dosage adjustments depend on the disease being treated with upadacitinib and the recommended dose for treatment of the particular disease in the absence and the presence of renal impairment. Thus, in some embodiments, the methods disclosed herein include reducing or maintaining the dose of upadacitinib. In some embodiments, the methods disclosed herein include reducing the recommended daily dose of upadacitinib from 45 mg to 30 mg, or from 30 mg to 15 mg, in patients with renal impairment. In some embodiments, the methods disclosed herein include maintaining the recommended daily dose of upadacitinib at 15 mg in patients with renal impairment.

[0176] For patients receiving upadacitinib for the treatment of rheumatoid arthritis or psoriatic arthritis in the absence of any renal impairment, the recommended daily dosage is 15 mg. For patients receiving upadacitinib for the treatment of rheumatoid arthritis or psoriatic arthritis, the patient has mild, moderate, and severe renal impairment, and the recommended dosage is 15 mg once daily. Thus, in some embodiments, the methods disclosed herein comprise maintaining a recommended daily dosage of upadacitinib of 15 mg.

[0177] In some embodiments, for patients receiving upadacitinib for the treatment of atopic dermatitis in the absence of any renal impairment, the recommended daily dose is 15 mg. In some embodiments, for patients receiving upadacitinib for the treatment of atopic dermatitis in the absence of any renal impairment, the recommended daily dose is 30 mg once daily.

[0178] Patients receiving upadacitinib for the treatment of atopic dermatitis have mild or moderate renal dysfunction (estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73 m 2For patients with atopic dermatitis, the recommended daily dose is 15 mg once daily. Accordingly, in some embodiments, the methods disclosed herein comprise maintaining a recommended daily dose of upadacitinib at 15 mg. For patients with atopic dermatitis, who are receiving upadacitinib for the treatment of atopic dermatitis, and who have severe renal impairment (eGFR<30 mL / min / 1.73 m 2 For patients who also have atopic dermatitis and end stage renal disease (eGFR<15 mL / min / 1.73 m), the recommended daily dosage is 15 mg once daily. Accordingly, in some embodiments, the methods disclosed herein comprise maintaining a recommended daily dosage of upadacitinib at 15 mg. In some embodiments, the methods disclosed herein comprise reducing the recommended daily dose of upadacitinib from 30 mg to 15 mg. 2 ), the use of upadacitinib is not recommended for patients with

[0179] For patients receiving upadacitinib for the treatment of ulcerative colitis in the absence of any renal impairment, the recommended daily dose is an induction dose of 45 mg once daily for 8 weeks, followed by a maintenance dose of 15 mg once daily, or for patients with refractory, severe, or extensive disease, 30 mg once daily. Patients receiving upadacitinib for the treatment of ulcerative colitis who have mild or moderate renal impairment (eGFR ≥ 30 mL / min / 1.73 m 2 For patients with refractory rheumatoid arthritis, the recommended dosage is 45 mg once daily for induction and 30 mg once daily for maintenance. Thus, in some embodiments, the methods disclosed herein comprise maintaining the recommended induction and maintenance daily doses of upadacitinib (45 mg and either 15 mg or 30 mg, respectively).

[0180] He was receiving upadacitinib for the treatment of ulcerative colitis and had severe renal dysfunction (eGFR < 30 mL / min / 1. 73m2), the recommended induction dose is 30 mg once daily for 8 weeks and the recommended maintenance dose is 15 mg once daily. Thus, in some embodiments, the methods disclosed herein comprise reducing the recommended daily induction dose of upadacitinib from 45 mg to 30 mg. In some embodiments, the methods disclosed herein comprise reducing the recommended daily maintenance dose of upadacitinib from 30 mg to 15 mg. In some embodiments, the methods disclosed herein comprise maintaining a recommended daily maintenance dose of upadacitinib at 15 mg. Ulcerative colitis and end stage renal disease (eGFR<15 mL / min / 1.73 m 2 ), the use of upadacitinib is not recommended for patients with

[0181] In some embodiments, the daily dose of 30 mg is maintained and the dose of 30 mg is administered without caution, in some embodiments, the reduced daily dose of 30 mg is administered without caution.

[0182] In some embodiments, the daily dose of 30 mg is maintained and the patient is closely monitored for adverse reactions. In some embodiments, a reduced daily dose of 30 mg is administered and the patient is closely monitored for adverse reactions.

[0183] In some embodiments, the daily dose of 15 mg is maintained and the dose of 15 mg is administered without caution, in some embodiments, the reduced daily dose of 15 mg is administered without caution.

[0184] In some embodiments, the daily dose of 15 mg is maintained and the patient is closely monitored for adverse reactions. In some embodiments, a reduced daily dose of 15 mg is administered and the patient is closely monitored for adverse reactions.

[0185] In any of the above embodiments, it is contemplated herein that the 30 mg dose may be administered as two 15 mg dosage forms.

[0186] Upadacitinib Dosing in Subjects with Hepatic Impairment When upadacitinib is administered to patients with hepatic impairment, the recommended upadacitinib dose may differ from the recommended dose in the absence of hepatic impairment. Dosage adjustments depend on the disease being treated with upadacitinib and the doses recommended for treatment of the specific disease in the absence and extent of hepatic impairment. Upadacitinib is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

[0187] For patients receiving upadacitinib for the treatment of rheumatoid arthritis or psoriatic arthritis in the absence of any hepatic impairment, the recommended daily dosage is 15 mg. For patients receiving upadacitinib for the treatment of rheumatoid arthritis or psoriatic arthritis and the patient has mild or severe hepatic impairment, the recommended dosage is 15 mg once daily. Thus, in some embodiments, the methods disclosed herein comprise maintaining a recommended daily dose of upadacitinib of 15 mg.

[0188] In some embodiments, for patients receiving upadacitinib for the treatment of atopic dermatitis in the absence of any hepatic impairment, the recommended daily dosage is 15 mg. In some embodiments, for patients receiving upadacitinib for the treatment of atopic dermatitis in the absence of any hepatic impairment, the recommended daily dosage is 30 mg once daily. For patients receiving upadacitinib for the treatment of atopic dermatitis who also have mild or moderate hepatic impairment, the recommended dosage is 15 mg once daily. Thus, in some embodiments, the methods disclosed herein include maintaining a recommended daily dosage of upadacitinib at 15 mg. In some embodiments, the methods disclosed herein include maintaining a recommended daily dose of upadacitinib at 30 mg.

[0189] For patients receiving upadacitinib for the treatment of ulcerative colitis in the absence of any hepatic impairment, the recommended daily dose is an induction dose of 45 mg once daily for 8 weeks, followed by a maintenance dose of 15 mg once daily, or for patients with refractory, severe, or extensive disease, 30 mg once daily. For patients receiving upadacitinib for the treatment of ulcerative colitis who also have mild or moderate hepatic impairment, the recommended induction dose is 30 mg once daily for 8 weeks, and the recommended maintenance dose is 15 mg once daily. Thus, in some embodiments, the methods disclosed herein include reducing the recommended daily induction dose of upadacitinib from 45 mg to 30 mg. In some embodiments, the methods disclosed herein include reducing the recommended daily maintenance dose of upadacitinib from 30 mg to 15 mg. In some embodiments, the methods disclosed herein comprise maintaining the recommended daily maintenance dose of upadacitinib at 15 mg.

[0190] In some embodiments, the daily dose of 30 mg is maintained and the dose of 30 mg is administered without caution, in some embodiments, the reduced daily dose of 30 mg is administered without caution.

[0191] In some embodiments, the daily dose of 30 mg is maintained and the patient is closely monitored for adverse reactions. In some embodiments, a reduced daily dose of 30 mg is administered and the patient is closely monitored for adverse reactions.

[0192] In some embodiments, the daily dose of 15 mg is maintained and the dose of 15 mg is administered without caution, in some embodiments, the reduced daily dose of 15 mg is administered without caution.

[0193] In some embodiments, the daily dose of 15 mg is maintained and the patient is closely monitored for adverse reactions. In some embodiments, a reduced daily dose of 15 mg is administered and the patient is closely monitored for adverse reactions.

[0194] In any of the above embodiments, it is contemplated herein that the 30 mg dose may be administered as two 15 mg dosage forms. EXAMPLES

[0195] Examples 1 and 2 provide prescribing information for RINVOQ® (upadacitinib).

[0196] Example 1. RINVOQ Prescribing Information Prescribing information highlights These highlights do not contain all the information needed to use RINVOQ® safely and effectively. See full prescribing information for RINVOQ®. RINVOQ® (upadacitinib) extended-release tablets for oral, Initial U.S. Approval: 2019. WARNINGS: Serious infections, mortality, malignancies, major adverse cardiovascular events (MACE) and thrombosis. See full prescribing information for complete boxed warning.

[0197] There is an increased risk of serious bacterial, fungal, viral and opportunistic infections, including tuberculosis (TB), leading to hospitalization or death. If a serious infection occurs, interrupt treatment with RINVOQ® until the infection is controlled. Test for latent TB before and during therapy; treat latent TB before use. Monitor all patients for active TB during treatment, and further monitor patients with an initial, negative latent TB test.

[0198] In patients with rheumatoid arthritis (RA), another Janus kinase (JAK) inhibitor versus a tumor necrosis factor (TNF) blocker is associated with higher all-cause mortality, including sudden cardiovascular death.

[0199] Malignancies have occurred in patients treated with RINVOQ®. High rates of lymphoma and lung cancer in RA patients with other JAK inhibitors vs. TNF blockers.

[0200] In patients with RA, there is a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with another JAK inhibitor vs. TNF blocker.

[0201] Thrombosis has occurred in patients treated with RINVOQ®. Increased incidence of pulmonary embolism, venous thrombosis, and arterial thrombosis with another JAK inhibitor vs. TNF blocker.

[0202] Indications and Usage RINVOQ® is a Janus kinase (JAK) inhibitor; It is indicated for the treatment of adults with moderate to severe active rheumatoid arthritis who have had an inadequate response to or intolerance to one or more TNF-blocking agents.

[0203] Restrictions on Use Use of RINVOQ® in combination with other JAK inhibitors, biologic DMARDs, or strong immunosuppressants such as azathioprine and cyclosporine is not recommended. Adults with psoriatic arthritis who have had an inadequate response to or who are intolerant to one or more TNF-blocking drugs.

[0204] Restrictions on Use Use of RINVOQ® in combination with other JAK inhibitors, biologic DMARDs, or strong immunosuppressants such as azathioprine and cyclosporine is not recommended. Adults and pediatric patients 12 years of age and older with moderate to severe refractory atopic dermatitis not adequately controlled with other systemic medicinal products, including biologics, or when the use of such therapies is undesirable.

[0205] Restrictions on Use RINVOQ® is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants.

[0206] DOSAGE and Administration Prior to treatment, immunizations should be updated and evaluation for active and latent tuberculosis, viral hepatitis, liver function, and pregnancy status should be considered. Absolute lymphocyte count should be 500 cells / mL or higher. / mm 3 Absolute neutrophil count is less than 1000 cells / mm 3 Avoid initiating or discontinuing RINVOQ® if blood glucose levels are below 100 mg / dL or hemoglobin levels are below 8 g / dL.

[0207] Rheumatoid arthritis The recommended dose of RINVOQ® is 15 mg taken once daily.

[0208] Psoriatic arthritis The recommended dose of RINVOQ® is 15 mg taken once daily.

[0209] Atopic dermatitis Pediatric patients aged 12 years or older weighing at least 40 kg and adults under 65 years of age: Initiate treatment with 15 mg orally once daily. If there is no adequate response, consider increasing the dose to 30 mg orally once daily. Adults 65 years and older: The recommended dose is 15 mg once daily. Severe renal impairment: The recommended dose is 15 mg once daily.

[0210] Dosage form and strength Extended release tablets: 15 mg and 30 mg.

[0211] contraindication Known hypersensitivity to upadacitinib or to any of the excipients in RINVOQ®.

[0212] Warnings and Cautions Serious Infections: Avoid the use of RINVOQ® in patients with active serious infections, including localized infections. Hypersensitivity: Severe hypersensitivity reactions (e.g., anaphylaxis) have been reported. Discontinue administration of RINVOQ® if a severe hypersensitivity reaction occurs. Gastrointestinal (GI) Perforation: Monitor patients at risk for GI perforation and promptly evaluate symptomatic patients. Laboratory Abnormalities: Monitoring is recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Embryo-Fetal Toxicity: RINVOQ® may cause fetal harm based on animal studies. Advise female patients of reproductive potential of the potential risk to the fetus and to use effective contraception. Vaccination: Avoid use of RINVOQ® with live vaccines.

[0213] Adverse Reactions Rheumatoid Arthritis and Psoriatic Arthritis: Adverse reactions (≥1%) were upper respiratory tract infection, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, and acne. Atopic dermatitis: Adverse reactions (≥ 1%) were upper respiratory tract infection, acne, herpes simplex, headache, increased blood creatine phosphokinase, cough, hypersensitivity, folliculitis, nausea, abdominal pain, fever, weight gain, herpes zoster, influenza, fatigue, neutropenia, myalgia, and influenza-like illness.

[0214] Drug interactions Strong CYP3A4 Inhibitors: The recommended dose of RINVOQ® in patients taking a strong CYP3A4 inhibitor is 15 mg once daily. Strong CYP3A4 inducers: Coadministration of RINVOQ® with strong CYP3A4 inducers is not recommended.

[0215] Use in Special Populations Lactation: Advise against breast-feeding. Hepatic Impairment: RINVOQ® is not recommended in patients with severe hepatic impairment.

[0216] Full Prescribing Information WARNING: SERIOUS INFECTIONS, MORTALITY, MAJOR ADVERSE CARDIOVASCULAR EVENTS AND THROMBOSIS

[0217] Serious infections Patients treated with RINVOQ® are at high risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking immunosuppressive drugs at the same time, such as methotrexate or corticosteroids. If a serious infection develops, RINVOQ® is discontinued until the infection is controlled. Reported infections include: Active tuberculosis, which may manifest as pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before using RINVOQ® and during therapy. Treatment for latent infection should be considered before using RINVOQ®. Invasive fungal infections, including cryptococcosis and pneumocystiosis. Bacterial, viral, including herpes zoster, and other infections caused by opportunistic pathogens.

[0218] The risks and benefits of treatment with RINVOQ® should be carefully considered before initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RINVOQ®, including the possible development of tuberculosis in patients who have tested negative for latent tuberculosis infection before initiating therapy.

[0219] mortality rate In a large randomized postmarketing safety trial comparing another Janus kinase (JAK) inhibitor with a tumor necrosis factor (TNF) blocker in rheumatoid arthritis (RA) patients aged 50 years or older with at least one cardiovascular risk factor, a higher overall mortality rate, including sudden cardiovascular death, was observed with the JAK inhibitor.

[0220] Malignant tumors Lymphomas and other malignancies have been observed in patients treated with RINVOQ®. A higher incidence of malignancies (excluding non-melanoma skin cancer (NMSC)) has been observed in RA patients treated with another JAK inhibitor when compared to TNF blockers. Current or former smokers are at even higher risk.

[0221] Major adverse cardiovascular events In RA patients aged 50 years or older with at least one cardiovascular risk factor treated with other JAK inhibitors, higher rates of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) have been observed when compared with TNF blockers. Current or former smokers are at even higher risk. Discontinue RINVOQ® in patients experiencing a myocardial infarction or stroke.

[0222] thrombosis Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, has occurred in patients treated with JAK inhibitors used to treat inflammatory conditions. Many of these adverse events have been serious, and some have been fatal. A higher incidence of thrombosis has been observed in RA patients aged 50 years or older with at least one cardiovascular risk factor treated with other JAK inhibitors, when compared with TNF blockers. Avoid RINVOQ® in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ® and be promptly evaluated.

[0223] Indications and Usage Rheumatoid arthritis RINVOQ® (upadacitinib) is indicated for the treatment of adults with moderate to severe active rheumatoid arthritis who have had an inadequate response to or intolerance to one or more TNF-blocking agents.

[0224] Limitations of Use: The use of RINVOQ® in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or strong immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

[0225] Psoriatic arthritis RINVOQ® is indicated for the treatment of adults with active psoriatic arthritis who have had an inadequate response to or intolerance to one or more TNF-blocking agents.

[0226] Limitations of Use: Use of RINVOQ® in combination with other JAK inhibitors, biologic DMARDs, or strong immunosuppressants such as azathioprine and cyclosporine is not recommended.

[0227] Atopic dermatitis RINVOQ® is indicated for the treatment of adult and pediatric patients 12 years of age and older with refractory moderate to severe atopic dermatitis that is not adequately controlled with other systemic medicinal products, including biologics, or when the use of such therapies is undesirable.

[0228] Limitations of Use: RINVOQ® is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants.

[0229] DOSAGE and Administration Recommended evaluations and vaccinations prior to initiating treatment Prior to initiating treatment with RINVOQ®, consider performing the following evaluations: Assessment for active and latent tuberculosis (TB) infection - if positive, treat TB before using RINVOQ®. Screen for viral hepatitis according to clinical guidelines - Initiation of RINVOQ® is not recommended in patients with active hepatitis B or C. Complete blood count - absolute lymphocyte count 500 cells / mm 3 Absolute neutrophil count less than 1000 cells / mm3 Initiation of RINVOQ® is not recommended for patients with a blood glucose level below 18.5 mg / dL or hemoglobin level below 8 g / dL. Baseline hepatic function: Initiation of RINVOQ® is not recommended in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy Status: Verify pregnancy status in females of reproductive potential prior to initiating treatment. · Update immunizations according to current immunization guidelines.

[0230] Important Dosing Instructions RINVOQ® tablets should be taken orally with or without food.

[0231] RINVOQ® tablets should be taken whole. RINVOQ® should not be split, crushed, or chewed.

[0232] Recommended Dosage for Rheumatoid Arthritis The recommended dose of RINVOQ® is 15 mg taken once daily.

[0233] Dosage recommendations for psoriatic arthritis The recommended dose of RINVOQ® is 15 mg taken once daily.

[0234] Recommended Dosage for Atopic Dermatitis Pediatric patients 12 years of age or older weighing at least 40 kg and adults under 65 years of age: Initiate treatment with 15 mg once daily. If adequate response is not achieved, consider increasing dose to 30 mg once daily. If adequate response is not achieved at the 30 mg dose, discontinue RINVOQ. Use the lowest effective dose needed to maintain response. Adults 65 years and older: The recommended dose is 15 mg once daily.

[0235] Recommended Dosage in Patients with Renal or Severe Hepatic Impairment Renal dysfunction Rheumatoid and psoriatic arthritis: No dose adjustment is necessary for patients with mild, moderate, or severe renal impairment. Atopic dermatitis: For patients with severe renal impairment [creatinine clearance (CrCL) < 30 mL / min], the recommended dose is 15 mg once daily. No dose adjustment is necessary for patients with mild or moderate renal impairment [(CrCL) > 30 mL / min].

[0236] Liver dysfunction RINVOQ® is not recommended for use in patients with severe hepatic impairment

[0237] Dosage Adjustments Due to Drug Interactions The recommended dose in patients receiving a strong CYP3A4 inhibitor is 15 mg once daily.

[0238] Dose interruption infectious disease If a patient develops a serious infection, including a serious opportunistic infection, interrupt RINVOQ® treatment until the infection is controlled.

[0239] [Table 1]

[0240] Management of laboratory abnormalities may require interruption of medication, as described in Table 1.

[0241] Dosage form and strength Extended release tablets: · 15mg: Purple, biconvex oblong, 14 x 8mm in size, with "a15" debossed on one side. · 30mg: Red, biconvex oblong, 14x8mm in size, with “a30” debossed on one side.

[0242] contraindication RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients.

[0243] Warnings and Cautions Serious infections Serious, sometimes fatal, infections have been reported in patients receiving RINVOQ®. The most frequent serious infections reported with RINVOQ® include pneumonia and cellulitis. Among other opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral / esophageal candidiasis, and cryptococcosis have been reported with RINVOQ®. Avoid use of RINVOQ® in patients with active serious infections, including localized infections.

[0244] Patients with chronic or recurrent infections Patients who have been exposed to tuberculosis Patients with a history of serious infections or opportunistic infections Patients who have lived in or traveled to areas with endemic tuberculosis or endemic mycoses; or Before initiating RINVOQ in patients with underlying conditions that may predispose to infection, consider the risks and benefits of treatment.

[0245] Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ®. If a patient develops a serious or opportunistic infection, discontinue RINVOQ®. Patients who develop a new infection while on treatment with RINVOQ® should undergo prompt and complete diagnostic testing appropriate for immunocompromised patients; appropriate antimicrobial therapy should be initiated and the patient should be closely monitored, and if the patient does not respond to antimicrobial therapy, RINVOQ® should be discontinued. Once the infection is controlled, RINVOQ® can be resumed.

[0246] tuberculosis Prior to administration of RINVOQ®, patients should be evaluated and tested for latent and active tuberculosis (TB) infection. Patients with latent TB should be treated with standard antimycobacterial therapy before initiating RINVOQ®. RINVOQ® should not be administered to patients with active TB. In patients with previously untreated latent or active TB where an appropriate course of treatment cannot be identified, and in patients who test negative for latent TB but have risk factors for TB infection, anti-TB therapy should be considered prior to initiating RINVOQ®. Consultation with a physician with expertise in the treatment of TB is recommended to help determine whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients for the development of signs and symptoms of TB while using RINVOQ®, including patients who have tested negative for latent TB infection prior to initiating therapy.

[0247] Viral reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, has been reported in clinical trials of RINVOQ®. The risk of herpes zoster appears to be high in patients treated with RINVOQ® in Japan. If a patient develops herpes zoster, consider temporary interruption of RINVOQ® until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed according to clinical guidelines before initiating and during therapy with RINVOQ. Patients who tested positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical trials. Patients who tested 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 phase 3 clinical trials of RINVOQ. If hepatitis B virus DNA is detected while receiving RINVOQ®, a hepatologist should be consulted.

[0248] mortality rate In another large randomized post-marketing safety study of a JAK inhibitor in RA patients aged 50 years or older with at least one cardiovascular risk factor, a higher overall mortality rate, including sudden cardiovascular death, was observed in patients treated with JAK inhibitors compared with TNF blockers. Consider the benefits and risks for each individual patient before initiating or continuing therapy with RINVOQ®.

[0249] Malignant tumors and lymphoproliferative disorders Malignancies, including lymphoma, were observed in clinical trials of RINVOQ®. In a large randomized post-marketing safety study of another JAK inhibitor in RA patients, the incidence of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed to be higher in patients treated with JAK inhibitors compared to patients treated with TNF blockers. The incidence of lymphoma was observed to be higher in patients treated with JAK inhibitors compared to patients treated with TNF blockers. The incidence of lung cancer was observed to be higher in smokers currently or formerly treated with JAK inhibitors compared to smokers treated with TNF blockers. In this study, current or former smokers had an even higher overall risk of malignancies. Before initiating or continuing therapy with RINVOQ®, consider the benefits and risks for each individual patient, especially those with known malignancies (excluding successfully treated NMSC), those who develop malignancies during treatment, and those who are current or former smokers.

[0250] Nonmelanoma skin cancer NMSC has been reported in patients treated with RINVOQ®. Regular skin examinations are recommended for patients at high risk for skin cancer. Exposure to sunlight and UV rays should be limited by wearing protective clothing and using broad-spectrum sunscreens.

[0251] Major adverse cardiovascular events In a large randomized post-marketing safety study of another JAK inhibitor in RA patients aged 50 years or older with at least one cardiovascular risk factor, the rate of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, was observed to be higher in patients treated with JAK inhibitors compared to those treated with TNF blockers. Current or former smokers are at even higher risk. Before initiating or continuing therapy with RINVOQ®, consider the benefits and risks for each individual patient, especially those who are current or former smokers and those with other cardiovascular risk factors. Patients should be informed of the symptoms of serious cardiovascular events and the steps to take if the event occurs. Discontinue RINVOQ® in patients experiencing myocardial infarction or stroke.

[0252] thrombosis Thrombosis, including deep vein thrombosis (DVT), pulmonary embolism (PE) and arterial thrombosis, has occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ®. Many of these adverse events have been serious and some have been fatal. In a large randomized post-marketing safety study of another JAK inhibitor in RA patients aged 50 years or older with at least one cardiovascular risk factor, a higher incidence of total thrombosis, DVT and PE was observed compared to patients treated with TNF blockers. If symptoms of thrombosis occur, patients should discontinue RINVOQ® and be promptly evaluated and appropriately treated. Avoid RINVOQ® in patients at risk of increased thrombosis risk.

[0253] Hypersensitivity reactions In clinical trials, serious hypersensitivity reactions, e.g., anaphylaxis and angioedema, have been reported in patients receiving RINVOQ®. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ® and initiate appropriate therapy.

[0254] Gastrointestinal perforation Gastrointestinal perforation has been reported in clinical trials with RINVOQ®, in which many of the patients with rheumatoid arthritis were receiving background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs).

[0255] Monitor patients treated with RINVOQ® who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Promptly evaluate patients presenting with new-onset abdominal pain for early identification of gastrointestinal perforation.

[0256] Abnormal laboratory test results Neutropenia Treatment with RINVOQ® was associated with a decline in neutropenia (ANC below 1000 cells / mm 3 Neutrophil counts should be assessed at baseline and thereafter according to routine patient management. Patients with low neutrophil counts (i.e., ANC < 1000 cells / mm 3 Avoid initiating RINVOQ and discontinue RINVOQ treatment in patients with pulmonary embolism (less than 18 days after onset of pulmonary embolism).

[0257] Lymphocytopenia ALC is 500 cells / mm 3 Lymphocyte counts less than 500 cells / mm3 have been reported in patients treated with RINVOQ® in clinical trials. Lymphocyte counts should be assessed at baseline and thereafter according to routine patient care. Patients with low lymphocyte counts (i.e., less than 500 cells / mm3) should be monitored for lymphocyte counts. 3 Avoid initiating RINVOQ and discontinue RINVOQ treatment in patients with pulmonary embolism (less than 18 days after onset of pulmonary embolism).

[0258] anemia In clinical trials, declines in hemoglobin levels below 8 g / dL have been reported in patients treated with RINVOQ®. Assess hemoglobin at baseline and thereafter according to routine patient care. Avoid initiating RINVOQ® and discontinue RINVOQ® treatment in patients with low hemoglobin levels (i.e., <8 g / dL).

[0259] 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. Elevations in LDL cholesterol decreased to pretreatment levels in response to statin therapy. The impact of increases in these lipid parameters on cardiovascular morbidity and mortality has not been determined. Evaluate lipid parameters approximately 12 weeks after initiation of treatment and thereafter according to clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for management of hyperlipidemia.

[0260] Elevated liver enzymes Treatment with RINVOQ® was associated with an increased incidence of liver enzyme elevations compared to placebo treatment. Liver enzymes should be assessed at baseline and thereafter according to routine patient care. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If, during routine patient care, an increase in ALT or AST is observed and drug-induced liver injury is suspected, RINVOQ® should be discontinued until this diagnosis has been excluded.

[0261] Embryo-fetal toxicity Based on findings from animal studies, RINVOQ® may cause fetal harm when administered to pregnant women. Upadacitinib has been associated with increased fetal malformations when administered to rats and rabbits during the stage of organogenesis. Verify the pregnancy status of patients of reproductive potential prior to initiating treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with RINVOQ® and for 4 weeks after completing therapy.

[0262] Vaccination Avoid the use of live vaccines during or immediately prior to RINVOQ® therapy. Prior to initiating RINVOQ®, it is recommended that patients be up-to-date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccination, in accordance with current immunization guidelines.

[0263] Adverse Reactions The following clinically significant adverse reactions are described elsewhere in the labeling: Serious infections · Mortality rate Malignant tumors and lymphoproliferative disorders Major adverse cardiovascular events · thrombosis Hypersensitivity reactions · Gastrointestinal perforation Abnormal laboratory test results

[0264] Clinical trial experience Because clinical trials are conducted under a wide variety of conditions, the adverse reaction rates observed in clinical trials of one drug may not be directly comparable to the adverse reaction rates observed in clinical trials of another drug and may not reflect the rates actually observed.

[0265] Adverse Reactions in Patients with Rheumatoid Arthritis A total of 3833 patients with rheumatoid arthritis were treated with upadacitinib in Phase 3 clinical trials, of which 2806 patients were exposed for at least 1 year. Depending on the study design, patients could transition or switch from placebo to RINVOQ® 15 mg or seek relief from active comparator or placebo to RINVOQ® as early as week 12. A total of 2630 patients received at least one dose of RINVOQ® 15 mg, of which 1860 patients were exposed for at least 1 year. In the RA-I, RA-II, RA-III and RA-V studies, 1213 patients received at least one dose of RINVOQ® 15 mg, of which 986 patients were exposed for at least 1 year, and 1203 patients received at least one dose of upadacitinib 30 mg, of which 946 patients were exposed for at least 1 year.

[0266] [Table 2]

[0267] Other adverse reactions reported in <1% of patients in the RINVOQ® 15 mg group and at higher rates in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (including oral herpes), and oral candidiasis. In the Specific Adverse Reactions section, four pooled data sets are presented: Placebo-Controlled Studies: The RA-III, RA-IV, and RA-V studies were combined to represent safety through weeks 12 / 14 for placebo (n=1042) and RINVOQ® 15 mg (n=1035). The RA-III and RA-V studies were combined to represent safety through week 12 for placebo (n=390), RINVOQ® 15 mg (n=385), and upadacitinib 30 mg (n=384). The RA-IV study did not include a 30 mg dose, therefore safety data for upadacitinib 30 mg can only be compared to rates for placebo and RINVOQ 15 mg by pooling the RA-III and RA-V studies. MTX-Controlled Studies: RA-I and RA-II studies were combined to represent safety through weeks 12 / 14 for MTX (n=530), RINVOQ 15 mg (n=534), and upadacitinib 30 mg (n=529). 12-Month Exposure Dataset: RA-I, II, III, and V studies were combined to represent long-term safety for RINVOQ® 15 mg (n=1213) and upadacitinib 30 mg (n=1203). Exposure-adjusted incidence rates were adjusted by study for all adverse events reported in this section.

[0268] Specific Adverse Reactions infectious disease Placebo-controlled studies: In RA-III, RA-IV, and RA-V, infections were reported in 218 placebo-treated patients (95.7 per 100 patient-years) and 284 RINVOQ® 15 mg-treated patients (127.8 per 100 patient-years). In RA-III and RA-V, infections were reported in 99 placebo-treated patients (136.5 per 100 patient-years), 118 RINVOQ® 15 mg-treated patients (164.5 per 100 patient-years), and 126 upadacitinib 30 mg-treated patients (180.3 per 100 patient-years).

[0269] MTX-controlled studies: Infections were reported in 127 patients treated with MTX monotherapy (119.5 per 100 patient-years), in 104 patients treated with RINVOQ 15 mg monotherapy (91.8 per 100 patient-years), and in 128 patients treated with upadacitinib 30 mg monotherapy (115.1 per 100 patient-years).

[0270] 12-month Exposure Dataset: Infections were reported in 615 patients treated with RINVOQ® 15 mg (83.8 per 100 patient-years) and in 674 patients treated with upadacitinib 30 mg (99.7 per 100 patient-years).

[0271] Serious infections Placebo-controlled studies: In RA-III, RA-IV, and RA-V, serious infections were reported in 6 patients receiving placebo (2.3 per 100 patient-years) and 12 patients treated with RINVOQ® 15 mg (4.6 per 100 patient-years). In RA-III and RA-V, serious infections were reported in 1 patient receiving placebo (1.2 per 100 patient-years), 2 patients treated with RINVOQ® 15 mg (2.3 per 100 patient-years), and 7 patients treated with upadacitinib 30 mg (8.2 per 100 patient-years).

[0272] MTX-controlled studies: Serious infections were reported in 2 patients treated with MTX monotherapy (1.6 per 100 patient-years), 3 patients treated with RINVOQ® 15 mg monotherapy (2.4 per 100 patient-years), and 8 patients treated with upadacitinib 30 mg monotherapy (6.4 per 100 patient-years).

[0273] 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.

[0274] The most frequently reported serious infections were pneumonia and cellulitis.

[0275] tuberculosis Placebo- and MTX-controlled studies: During the placebo-controlled period, no active TB cases were reported in the placebo, RINVOQ® 15 mg, and upadacitinib 30 mg groups. During the MTX-controlled period, no active TB cases were reported in the MTX, RINVOQ® 15 mg, and upadacitinib 30 mg monotherapy groups.

[0276] 12-month Exposure Dataset: Active tuberculosis was reported in two patients treated with RINVOQ® 15 mg and one patient treated with upadacitinib 30 mg. Cases of extrapulmonary tuberculosis were reported.

[0277] Opportunistic infections (excluding tuberculosis) Placebo-controlled studies: In RA-III, RA-IV, and RA-V, opportunistic infections were reported in 3 patients receiving placebo (1.2 per 100 patient-years) and 5 patients treated with RINVOQ® 15 mg (1.9 per 100 patient-years). In RA-III and RA-V, opportunistic infections were reported in 1 patient receiving placebo (1.2 per 100 patient-years), 2 patients treated with RINVOQ® 15 mg (2.3 per 100 patient-years), and 6 patients treated with upadacitinib 30 mg (7.1 per 100 patient-years).

[0278] MTX-controlled studies: Opportunistic infections were reported in 1 patient treated with MTX monotherapy (0.8 per 100 patient-years), 0 patients treated with RINVOQ® 15 mg monotherapy, and 4 patients treated with upadacitinib 30 mg monotherapy (3.2 per 100 patient-years).

[0279] 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.

[0280] Malignant tumors Placebo-controlled studies: In RA-III, RA-IV, and RA-V, malignancies excluding NMSC were reported in 1 patient receiving placebo (0.4 per 100 patient-years) and 1 patient treated with RINVOQ® 15 mg (0.4 per 100 patient-years). In RA-III and RA-V, malignancies excluding NMSC were reported in 0 patients receiving placebo, 1 patient treated with RINVOQ 15 mg (1.1 per 100 patient-years), and 3 patients treated with upadacitinib 30 mg (3.5 per 100 patient-years).

[0281] MTX-controlled studies: 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.

[0282] 12-month Exposure Dataset: Malignancies excluding NMSC were reported in 13 patients treated with RINVOQ® 15 mg (1.2 per 100 patient-years) and 14 patients treated with upadacitinib 30 mg (1.3 per 100 patient-years).

[0283] Gastrointestinal perforation Placebo-Controlled Studies: (Based on medical review) No gastrointestinal perforations were reported in patients receiving placebo, patients treated with RINVOQ® 15 mg, or patients treated with upadacitinib 30 mg.

[0284] MTX-controlled study: No cases of gastrointestinal perforation were reported in the MTX and RINVOQ® 15 mg group through weeks 12 / 14. Two cases of gastrointestinal perforation were observed in the upadacitinib 30 mg group.

[0285] 12-month Exposure Dataset: Gastrointestinal perforation was reported in one patient treated with RINVOQ 15 mg and four patients treated with upadacitinib 30 mg.

[0286] thrombosis Placebo-controlled studies: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in one patient receiving placebo and one patient treated with RINVOQ® 15 mg. In RA-V, venous thrombosis was observed in one patient treated with RINVOQ® 15 mg. No cases of venous thrombosis were observed in RA-III. No cases of arterial thrombosis were observed up to week 12 / 14.

[0287] MTX-Controlled Studies: 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 weeks 12 / 14. 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.

[0288] 12-month Exposure Dataset: Venous thrombotic events were reported in 5 patients treated with RINVOQ® 15 mg (0.5 per 100 patient-years) and 4 patients treated with upadacitinib 30 mg (0.4 per 100 patient-years). Arterial thrombotic events were reported in 0 patients treated with RINVOQ® 15 mg and 2 patients treated with upadacitinib 30 mg (0.2 per 100 patient-years).

[0289] Abnormal laboratory test results Elevated liver transaminases In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), elevations of alanine transaminase (ALT) and aspartate transaminase (AST) ≥ 3x upper limit of normal (ULN) on at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ® 15 mg and 1.5% and 0.7% of patients receiving placebo, respectively, for up to 12 / 14 weeks. In RA-III and RA-V, elevations of ALT and AST ≥ 3x ULN on 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 1.3% and 1.0% of patients receiving placebo, respectively.

[0290] In MTX-controlled studies, elevations in ALT and AST ≥ 3 x ULN on at least one measurement for up to 12 / 14 weeks 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 1.9% and 0.9% of patients treated with MTX, respectively.

[0291] Elevated lipids Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides, and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Increases in LDL and HDL cholesterol peaked by week 8 and plateaued thereafter. In controlled studies, the changes from baseline in lipid parameters in patients treated with RINVOQ® 15 mg and upadacitinib 30 mg, respectively, up to 12 / 14 weeks 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.

[0292] In placebo-controlled trials (RA-III, RA-IV, and RA-V), dose-related increases in creatine phosphokinase (CPK) levels were observed with background DMARDs for up to 12 / 14 weeks. Elevations in CPK >5xULN were reported in 1.0% of patients in the RINVOQ® 15 mg group and 0.3% of patients in the placebo group over 12 / 14 weeks. Most increases >5xULN were transient and did not require treatment discontinuation. In RA-III and RA-V, increases in CPK >5xULN were observed in 0.3% of patients receiving placebo, 1.6% of patients treated with RINVOQ® 15 mg, and none in patients treated with upadacitinib 30 mg.

[0293] Neutropenia In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), patients had a mean plasma count of 1000 cells / mm3 or higher in at least one measurement for up to 12 / 14 weeks. 3 Dose-related decreases in neutrophil counts below 1000 cells occurred in 1.1% of patients in the RINVOQ® 15 mg group and <0.1% of patients in the placebo group. In RA-III and RA-V, neutrophil counts below 1000 cells on at least one measurement were / mm 3 Reductions below ANC occurred in 0.3% of patients receiving placebo, 1.3% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical trials, ANCs below 1000 cells were / mm 3 Treatment was discontinued when the

[0294] Lymphocytopenia In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), patients were randomized to receive at least one of the following treatments for up to 12 / 14 weeks: lymphocyte counts ≥ 500 cells / mL; / mm 3 Dose-related declines below 500 cells occurred in 0.9% of patients in the RINVOQ 15 mg group and 0.7% of patients in the placebo group. / mm 3 Reductions below 0.5% occurred in 0.5% of patients receiving placebo, 0.5% of patients treated with RINVOQ® 15 mg, and 2.4% of patients treated with upadacitinib 30 mg.

[0295] anemia In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), decreases in hemoglobin below 8 g / dL on at least one measurement occurred in <0.1% of patients in both the RINVOQ® 15 mg and placebo groups for up to 12 / 14 weeks. In RA-III and RA-V, decreases in hemoglobin below 8 g / dL on at least one measurement were observed in 0.3% of patients receiving placebo and in none of the patients treated with RINVOQ® 15 mg and upadacitinib 30 mg.

[0296] Adverse Reactions in Patients with Psoriatic Arthritis A total of 1827 patients with psoriatic arthritis were treated with upadacitinib in clinical trials, representing 1639.2 patient-years of exposure, of which 722 patients were exposed to upadacitinib for at least 1 year. In two Phase 3 studies, 907 patients received at least one dose of RINVOQ® 15 mg, of which 359 patients were exposed for at least 1 year. Two placebo-controlled studies were combined (640 patients treated with RINVOQ® 15 mg once daily, 635 patients receiving placebo) to evaluate the safety of RINVOQ® 15 mg compared to placebo up to 24 weeks after initiation of treatment. Overall, the safety profile observed in patients with active psoriatic arthritis treated with RINVOQ® 15 mg was consistent with that observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequency of herpes zoster and herpes simplex was >1% with RINVOQ® 15 mg (1.1% and 1.4%, respectively) and 0.8% and 1.3%, respectively, in the placebo group. Higher incidences of acne and bronchitis were observed in patients treated with RINVOQ® 15 mg (1.3% and 3.9%, respectively) compared with placebo (0.3% and 2.7%, respectively).

[0297] 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 studies 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 (range 12-75 years), and 13% of patients were aged 12-18 years. In these four studies, 2612 patients were treated orally once daily with RINVOQ® 15 mg or 30 mg, with or without 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 which 791 were exposed for at least 1 year, and 1246 patients received RINVOQ® 30 mg, of which 826 were exposed for at least 1 year. The AD-1, AD-2, and AD-4 studies compared the safety of RINVOQ® monotherapy with placebo through 16 weeks. The AD-3 study compared the safety of RINVOQ® + TCS with placebo + TCS through 16 weeks.

[0298] 0 to 16 weeks (AD-1 study to AD-4 study) In the RINVOQ® studies with and without TCS (Studies AD-1, 2, 3, and 4) through week 16, the percentage of patients who discontinued due to adverse reactions in the RINVOQ® 15 mg, 30 mg, and placebo groups was 2.3%, 2.9%, and 3.8%, respectively. Table 3 summarizes adverse reactions occurring at a rate of at least 1% during the first 16 weeks of treatment in the RINVOQ® 15 mg or 30 mg groups.

[0299] [Table 3]

[0300] Other adverse reactions reported in <1% of patients in the RINVOQ® 15 mg and / or 30 mg groups and at a higher incidence in the placebo group through week 16 included anemia, oral candidiasis, pneumonia, and 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 that in patients with RA. Other specific adverse reactions reported in patients with AD include eczema herpeticum / Kaposi's varicelliform eruption.

[0301] Herpetic eczema / Kaposi's varicelliform rash Placebo-controlled period (16 weeks): Eczema herpeticum was reported in 4 patients receiving placebo (1.6 per 100 patient-years), 6 patients treated with RINVOQ® 15 mg (2.2 per 100 patient-years), and 7 patients treated with RINVOQ® 30 mg (2.6 per 100 patient-years).

[0302] 12-month exposure (Weeks 0-52): Eczema herpeticum was reported in 18 patients (1.6 per 100 person-years) treated with RINVOQ® 15 mg and in 17 patients (1.5 per 100 person-years) treated with RINVOQ® 30 mg.

[0303] Drug interactions Strong CYP3A4 inhibitor Upadacitinib exposure is increased when RINVOQ® is coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole), which may increase the risk of adverse reactions from RINVOQ®. Closely monitor patients for adverse reactions when RINVOQ 15 mg once daily is coadministered with strong CYP3A4 inhibitors. Coadministration of RINVOQ® 30 mg once daily with strong CYP3A4 inhibitors is not recommended.

[0304] Strong CYP3A4 inducer Upadacitinib exposure is decreased when RINVOQ® is coadministered with strong CYP3A4 inducers (e.g., rifampin), which may reduce the therapeutic efficacy of RINVOQ®. Coadministration of RINVOQ® with strong CYP3A4 inducers is not recommended.

[0305] Use in Special Populations pregnancy Summary of risks Available data from the pharmacovigilance safety database and post-marketing case reports regarding the use of RINVOQ® in pregnant women are insufficient to assess the drug-associated risk of serious birth defects or miscarriage. Based on animal studies, RINVOQ® may cause adverse effects on the developing fetus. Advise reproductive and pregnant patients of the potential risk to the fetus. In animal embryo-fetal development studies, oral administration of upadacitinib to pregnant rats and rabbits at exposures equivalent to or greater than approximately 2 and 17 times the 15 mg dose and 0.9 and 8.5 times the maximum recommended human dose (MRHD) of 30 mg, respectively, resulted in a dose-related increase in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), an increased post-implantation defect (rabbits only), and reduced fetal weight in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib at approximately 0.3 and 2.5 times the 15 mg dose and 0.2 and 1.3 times the MRHD of 30 mg, respectively, during the period of organogenesis.In a pre- and postnatal developmental study in pregnant female rats, oral upadacitinib administered at an exposure approximately 1.6 times the MRHD of 30 mg did not result in maternal or developmental toxicity.

[0306] The background risks of serious birth defects and miscarriage in a given population are unknown. All pregnancies have a background risk of birth defects, defects, or other adverse outcomes. In the U.S. population, the estimated background risks of serious birth defects and miscarriage are 2-4% and 15-20%, respectively.

[0307] Clinical considerations Disease-related maternal and / or embryo / fetal risks Published data suggest that in women with rheumatoid arthritis, increased disease activity is associated with an increased risk of developing adverse pregnancy outcomes, including preterm delivery (before 37 weeks of gestation), low birth weight (<2500 g), and short gestational age at birth.

[0308] data Animal Data In an oral embryo-fetal development study, pregnant rats were administered upadacitinib at doses of 5, 25, and 75 mg / kg / day during organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations consisting of humeral deformity and scapular flexion) at exposures approximately 1.0-fold or greater than the MRHD of 30 mg (based on AUC at maternal oral doses of 5 mg / kg / day or greater). Additional skeletal malformations (forelimb / hindlimb flexion and rib / vertebral defects) and reduced fetal weight were observed in the absence of maternal toxicity at exposures approximately 48-fold the MRHD of 30 mg (based on AUC at maternal oral doses of 75 mg / kg / day).

[0309] In a second oral embryo-fetal development study, pregnant rats were administered upadacitinib at doses of 1.5 and 4 mg / kg / day during organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations including humeral and scapular flexion) at exposures approximately 0.9-fold the MRHD of 30 mg (based on AUC at a maternal oral dose of 4 mg / kg / day). No developmental toxicity was observed in rats at exposures approximately 0.2-fold the MRHD of 30 mg (based on AUC at a maternal oral dose of 1.5 mg / kg / day).

[0310] In an oral embryo-fetal development study, pregnant rabbits were administered upadacitinib at doses of 2.5, 10, and 25 mg / kg / day during organogenesis from day 7 to day 19 of gestation. Embryonic lethality, reduced fetal weight, and cardiovascular malformations were observed in the presence of maternal toxicity at exposures approximately 8.5-fold higher than the MRHD of 30 mg (based on AUC at a maternal oral dose of 25 mg / kg / day). Embryonic lethality consisted of increased post-implantation losses due to increased incidence of total and early resorptions. Developmental toxicity was not observed in rabbits at exposures approximately 1.3-fold higher than the MRHD of 30 mg (based on AUC at a maternal oral dose of 10 mg / kg / day).

[0311] In a pre- and postnatal oral developmental study, pregnant female rats were administered 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 the mothers or pups, respectively, at exposures approximately 1.6-fold the MRHD of 30 mg (based on AUC at a maternal oral dose of 10 mg / kg / day).

[0312] Breastfeeding Summary of risks There are no data regarding the presence of upadacitinib in human milk, its effects on breast-fed infants, or its effects on breast milk production. Available pharmacodynamic / toxicology data in animals indicate excretion of upadacitinib in milk (see Data). When a drug is present in animal milk, it may be present in human milk. Advise patients that breast-feeding is not recommended during treatment with RINVOQ® and for 6 days (approximately 10 half-lives) after the final dose due to the potential for serious adverse reactions in breast-fed infants.

[0313] data Lactating female Sprague-Dawley rats were administered a single oral dose of radiolabeled upadacitinib at 10 mg / kg on postpartum days 7-8. Drug exposure was measured using the AUC 0-t Based on the values, approximately 30-fold more was found in milk than in maternal plasma. Approximately 97% of the drug-related substances in milk were the parent drug. Women and men of reproductive potential Pregnancy test Verify pregnancy status in females of reproductive potential prior to initiating treatment with RINVOQ®.

[0314] contraception woman Based on animal studies, upadacitinib can cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with RINVOQ® and for 4 weeks after the final dose.

[0315] Pediatric Use Juvenile idiopathic arthritis and psoriatic arthritis The safety and effectiveness of RINVOQ® in pediatric patients with juvenile idiopathic arthritis and psoriatic arthritis have not been established.

[0316] Atopic dermatitis The safety and efficacy of RINVOQ® in pediatric patients aged 12 years or older weighing at least 40 kg with atopic dermatitis has been established. A total of 344 pediatric patients aged 12-17 years with moderate to severe atopic dermatitis were randomized into three studies (AD-1, AD-2, and AD-3) to receive either RINVOQ® 15 mg (N=114) or 30 mg (N=114) or a matching dose of placebo (N=116) as monotherapy or in combination with topical corticosteroids. Efficacy was consistent between pediatric and adult patients. The adverse reaction profile in pediatric patients was similar to that in adults. The safety and efficacy of RINVOQ® in pediatric patients less than 12 years old with atopic dermatitis has not been established.

[0317] Use in the elderly Rheumatoid arthritis and psoriatic arthritis Of the 4381 patients treated in the five clinical trials, a total of 906 rheumatoid arthritis patients were 65 years of age or older, including 146 patients aged 75 years or older. Of the 1827 patients treated in the two psoriatic arthritis Phase 3 clinical trials, a total of 274 patients were 65 years of age or older, including 34 patients aged 75 years or older. No differences in efficacy were observed between these patients and younger patients; however, there was a higher incidence of overall adverse events, including serious infections, in patients aged 65 years or older.

[0318] Atopic dermatitis Of 2583 patients treated in three phase 3 clinical trials, a total of 120 patients with atopic dermatitis were aged 65 years or older, including 6 patients aged 75 years. No differences in efficacy were observed between these patients and younger patients; however, in the long-term treatment trials, there was a higher incidence of serious infections and malignancies in patients aged 65 years or older in the 30 mg dose group.

[0319] Renal dysfunction For patients with rheumatoid arthritis and psoriatic arthritis, no dose adjustment is required in patients with mild, moderate, or severe renal impairment.

[0320] For patients with atopic dermatitis, the maximum recommended dose is 15 mg once daily for patients with severe renal impairment (CrCL<30 mL / min). No dose adjustment is required in patients with mild or moderate renal impairment.

[0321] The use of RINVOQ® has not been studied in patients with end-stage renal disease and therefore is not recommended for use in this population [see Clinical Pharmacology (12.3)].

[0322] Liver dysfunction No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). The use of RINVOQ® has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and therefore use in this population is not recommended.

[0323] explanation RINVOQ® contains upadacitinib, a JAK inhibitor. Upadacitinib has the chemical name: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1). The strength of upadacitinib is based on anhydrous upadacitinib. The solubility of upadacitinib in water is 38-0.2 mg / mL at 37°C in the pH range of 2-9. Upadacitinib has a molecular weight of 389.38 g / mol and a molecular formula of C 17 H 19 F3N6O - 1 / 2H2O. The chemical structure of upadacitinib is:

[0324] [ka] It is.

[0325] RINVOQ® 15 mg extended-release tablets for oral administration are purple, biconvex, oblong, measuring 14×8 mm, with "a15" debossed on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, triferric oxide, hypromellose, red ferric oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid, and titanium dioxide.

[0326] RINVOQ® 30 mg extended-release tablets for oral administration are red, biconvex, oblong, measuring 14×8 mm, with "a30" debossed on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, red iron oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid, and titanium dioxide.

[0327] Clinical Pharmacology Mechanism of action Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit signals resulting from cytokine or growth factor-receptor interactions on the cell membrane to affect cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which regulate intracellular activities, including gene expression. Upadacitinib regulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

[0328] JAK enzymes mediate cytokine signaling through their pairings (e.g., JAK1 / JAK2, JAK1 / JAK3, JAK1 / TYK2, JAK2 / JAK2, JAK2 / TYK2). In cell-free isolated enzyme assays, upadacitinib was more potent at inhibiting JAK1 and JAK2 than JAK3 and TYK2. In human white blood cell assays, upadacitinib inhibited cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1 / JAK3 more potently than STAT phosphorylation mediated by JAK2 / JAK2. However, the relevance of inhibition of specific JAK enzymes to therapeutic efficacy is currently unknown.

[0329] Pharmacodynamics Inhibition of IL-6-induced STAT3 and IL-7-induced STAT5 phosphorylation In healthy volunteers, administration of upadacitinib (immediate release formulation) resulted in dose- and concentration-dependent inhibition of IL-6 (JAK1 / JAK2)-induced STAT3 and IL-7 (JAK1 / JAK3)-induced STAT5 phosphorylation in whole blood, with maximal inhibition observed 1 hour after dosing and returning to near baseline by the end of the dosing interval.

[0330] Lymphocytes In patients with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline to week 36, which gradually returned to or near baseline levels with continued treatment.

[0331] Immunoglobulins In patients with rheumatoid arthritis, small decreases from baseline in mean IgG and IgM levels were observed with upadacitinib treatment during the control period, although mean values ​​at baseline and all visits were within normal reference ranges.

[0332] Cardiac Electrophysiology There were no clinically relevant effects on the QTc interval at six times the mean maximum exposure of the 15 mg once daily dose.

[0333] Pharmacokinetics Plasma exposure of upadacitinib is dose proportional across the therapeutic dose range. Steady-state plasma concentrations are achieved within 4 days, with minimal accumulation following multiple daily dosing. The pharmacokinetics of upadacitinib are similar in patients with rheumatoid arthritis, psoriatic arthritis, and atopic dermatitis.

[0334] absorption Following oral administration of the upadacitinib extended-release formulation, upadacitinib max Absorption occurs over a median time of 2 to 4 hours. Coadministration of a high-fat / high-calorie meal with upadacitinib had no clinically relevant effect on upadacitinib exposure (AUC inf is 29%, C max(39% increase in schizophrenia) In clinical trials, upadacitinib was administered without regard to food.

[0335] distribution Upadacitinib is 52% bound to plasma proteins. Upadacitinib distributes similarly between plasma and blood cellular components with a blood-to-plasma ratio of 1.0.

[0336] discharge metabolism Metabolism of upadacitinib is primarily mediated by CYP3A4 with a possible minor contribution from CYP2D6. The pharmacological activity of upadacitinib is attributable to the parent molecule. In human radiolabeling studies, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma, and the major metabolite detected (a product of mono-oxidation followed by glucuronidation) accounted for 13% of the total radioactivity in plasma. No active metabolites have been identified for upadacitinib.

[0337] Excretion [ 14 Following administration of a single dose of [C]-upadacitinib immediate-release solution, upadacitinib was primarily excreted in the urine (24%) and feces (38%) as unchanged parent substance. Approximately 34% of the upadacitinib dose was excreted as metabolites. The mean terminal elimination half-life of upadacitinib ranged from 8 to 14 hours.

[0338] Specific populations Weight, sex, race and age Weight, sex, race, ethnicity, and age had no clinically relevant effects on upadacitinib exposure.

[0339] Patients with renal dysfunction AUC of upadacitinib inf The C of upadacitinib was 18%, 33% and 44% higher in patients with mild, moderate and severe renal impairment, respectively, compared to patients with normal renal function. maxwere similar in patients with normal and impaired renal function. Mild or moderate renal impairment has no clinically relevant effect on upadacitinib exposure for the 15 mg or 30 mg once-daily dosing regimens. Severe renal impairment may increase the systemic exposure of upadacitinib after dosing at 30 mg once-daily in patients with atopic dermatitis. This may increase the risk of adverse reactions; therefore, dosage modifications are recommended in patients with severe renal impairment.

[0340] Patients with liver dysfunction Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment have no clinically relevant effect on upadacitinib exposure. AUC inf The C of upadacitinib was 28% and 24% higher in patients with mild and moderate renal impairment, respectively, compared with patients with normal liver function. max was unchanged in patients with mild hepatic impairment and 43% higher in patients with moderate hepatic impairment compared with patients with normal liver function. Upadacitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

[0341] Drug interaction studies Other drugs may affect the pharmacokinetics of upadacitinib Upadacitinib is metabolized in vitro by CYP3A4 with a minor contribution from CYP2D6. The effect of concomitant medications on upadacitinib plasma exposure is shown in Table 4.

[0342] [Table 4]

[0343] pH-modifying medicinal products (e.g., antacids or proton pump inhibitors) are not expected to affect the plasma exposure of upadacitinib based on in vitro assessments and population pharmacokinetic analysis. CYP2D6 metabolic phenotype had no effect on the pharmacokinetics of upadacitinib (based on population pharmacokinetic analysis), indicating that CYP2D6 inhibitors have no clinically relevant effect on upadacitinib exposure.

[0344] Potential for upadacitinib to affect the pharmacokinetics of other drugs In vitro studies have shown that upadacitinib does not inhibit or induce the activity of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at clinically relevant concentrations. In vitro studies have shown that upadacitinib does not inhibit the transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations.

[0345] Clinical trials have demonstrated that upadacitinib has no clinically relevant effects on the pharmacokinetics of concomitant medications. A summary of results from clinical trials evaluating the effect of upadacitinib on other medications is shown in Table 5.

[0346] [Table 5]

[0347] Non-clinical toxicology Carcinogenicity, mutagenicity and reproductive impairment Carcinogenesis The carcinogenic potential of upadacitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats treated with upadacitinib at oral doses of up to 15 mg / kg / day or 20 mg / kg / day, respectively (approximately 2.4- and 6.0-fold the MRHD of 30 mg, based on AUC, respectively) for up to 101 weeks. No evidence of tumorigenicity was observed in male or female Tg.rasH2 mice treated with upadacitinib orally at 20 mg / kg / day for 26 weeks.

[0348] Mutagenicity Upadacitinib has been tested in the following genotoxicity assays, with negative results: in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay.

[0349] Reproductive disorders Upadacitinib had no effect on fertility in male or female rats at oral doses of up to 50 mg / kg / day in males and 75 mg / kg / day in females (approximately 24-fold the MRHD of 30 mg in males and 48-fold the MRHD of 30 mg in females, based on AUC). However, maintenance of pregnancy was adversely affected at oral doses of 25 mg / kg / day and 75 mg / kg / day based on dose-related findings of increased post-implantation losses (increased resorptions) and reduced mean number of viable fetuses per litter (approximately 13-fold and 48-fold the AUC of the MRHD of 30 mg, respectively). The number of viable fetuses was not affected in female rats receiving upadacitinib orally at 5 mg / kg / day and mated to males receiving the same dose (approximately 1.0-fold the AUC of the MRHD of 30 mg).

[0350] Clinical Trials Rheumatoid arthritis The efficacy and safety of RINVOQ® 15 mg once daily was evaluated in five phase 3, randomized, double-blind, multicenter studies in patients with moderately to severely active rheumatoid arthritis fulfilling the ACR / EULAR 2010 classification criteria. Patients aged 18 years or older were eligible to participate. The presence of at least six tender and six swollen joints, and evidence of systemic inflammation based on elevated hsCRP, was required at baseline. The recommended dose of RINVOQ® is 15 mg once daily, although other doses have been studied.

[0351] RA-I (NCT02706873) was a 24-week monotherapy study in 947 patients with moderately to severely active rheumatoid arthritis naïve to methotrexate (MTX). Patients received RINVOQ 15 mg or upadacitinib 30 mg orally once daily or MTX as monotherapy. At week 26, patients unresponsive to upadacitinib could seek salvage with additional MTX and patients unresponsive to MTX could seek salvage with additional blinded RINVOQ 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients achieving an ACR50 response at week 12. Key secondary endpoints included Disease Activity Score (DAS28-CRP) ≤ 3.2 at week 12, DAS28-CRP < 2.6 at week 24, change from baseline in HAQ-DI at week 12, and change from baseline in van der Heijde-modified Total Sharpe Score (mTSS) at week 24.

[0352] RA-II (NCT02706951) was a 14-week monotherapy study in 648 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to MTX. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once-daily monotherapy or continued stable MTX monotherapy. At week 14, patients randomized to the MTX group were advanced to RINVOQ® 15 mg or upadacitinib 30 mg once-daily monotherapy in a blinded manner based on the allocation pre-determined at baseline. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 14. Key secondary endpoints included DAS28-CRP≦3.2, DAS28-CRP<2.6, and change from baseline in HAQ-DI at week 14.

[0353] RA-III (NCT02675426) was a 12-week study in 661 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARDs). Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily or placebo in addition to background cDMARD therapy. At week 12, patients randomized to placebo were advanced to RINVOQ® 15 mg or upadacitinib 30 mg once daily in a blinded manner based on the allocation pre-determined at baseline. The primary endpoint was the proportion of patients achieving an ACR20 response at week 12. Key secondary endpoints included DAS28-CRP≦3.2, DAS28-CRP<2.6, and change from baseline in HAQ-DI at week 12.

[0354] The RA-IV study (NCT02629159) was a 48-week study in 1629 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to MTX. Patients received RINVOQ® 15 mg once daily, an active comparator, or a placebo in addition to the MTX backbone. Beginning at week 14, patients not responding to RINVOQ® 15 mg could be rescued in a blinded manner with an active comparator, and patients not responding to either the active comparator or the placebo could be rescued in a blinded manner with RINVOQ® 15 mg. At week 26, all patients randomized to placebo were switched to RINVOQ® 15 mg once daily in a blinded manner. The primary endpoint was the proportion of patients vs. placebo who achieved an ACR20 response at week 12. Key secondary endpoints versus placebo included DAS28-CRP≦3.2, DAS28-CRP<2.6, change from baseline in HAQ-DI at week 12, and change from baseline in mTSS at week 26.

[0355] The RA-V study (NCT02706847) was a 12-week study in 499 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to biologic DMARDs. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily or placebo in addition to background cDMARD therapy. At week 12, patients randomized to placebo were advanced to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner based on the allocation pre-determined at baseline. The primary endpoint was the proportion of patients achieving an ACR20 response at week 12. Key secondary endpoints included DAS28-CRP ≦3.2 and change from baseline in HAQ-DI at week 12.

[0356] Clinical response The percentage of patients treated with RINVOQ® who achieved ACR20, ACR50 and ACR70 responses, as well as DAS28 (CRP) < 2.6 in all studies is shown in Table 6. Patients treated with RINVOQ® 15mg alone or in combination with cDMARDs achieved higher ACR response rates at the primary efficacy evaluation time point compared to MTX monotherapy or placebo, respectively (Table 6). The visit-by-visit proportion of patients who achieved ACR20 response in Study IV is shown in Figure 1. Higher ACR20 response rates were observed with RINVOQ 15mg vs. placebo at 1 week in the RA-III and RA-V studies. Treatment with RINVOQ 15mg alone or in combination with cDMARDs resulted in greater improvements in ACR components compared to MTX or placebo at the primary efficacy evaluation time point (Table 7).

[0357] [Table 6]

[0358] [Table 7] TIFF2025502266000009.tif73161

[0359] In RA-I and RA-IV, a higher proportion of patients treated with RINVOQ 15 mg alone or in combination with MTX achieved a DAS28-CRP < 2.6 at the primary efficacy evaluation time point compared with MTX or placebo (Table 8).

[0360] [Table 8]

[0361] Radiation Response Inhibition of progression of structural joint damage was assessed using the modified total Sharp score (mTSS) and its components erosion score and joint space narrowing score at week 26 in Study RA-IV and at week 24 in Study RA-I. The proportion of patients with radiographic freedom from progression (mTSS change from baseline ≤ 0) was also assessed.

[0362] In the RA-IV study, treatment with RINVOQ® 15 mg inhibited the progression of structural joint damage compared to placebo in combination with cDMARDs at week 26 (Table 9). Analysis of erosion scores and joint space narrowing scores was consistent with the overall results.

[0363] In the placebo + MTX group, 76% of patients were free of radiographic progression at 26 weeks compared to 83% of patients treated with RINVOQ® 15 mg.

[0364] In the RA-I study, treatment with RINVOQ® 15 mg monotherapy inhibited the progression of structural joint damage compared to MTX monotherapy and placebo in combination with cDMARDs at week 24 (Table 9). Analysis of erosion scores and joint space narrowing scores was consistent with the overall results.

[0365] In the MTX monotherapy group, 78% of patients were free of radiographic progression at 24 weeks compared to 87% of patients treated with RINVOQ® 15 mg monotherapy.

[0366] [Table 9]

[0367] Physical Function Response Treatment with RINVOQ® 15 mg alone or in combination with cDMARDs was associated with greater improvements in physical function at weeks 12 / 14 compared to all comparators as measured by HAQ-DI.

[0368] Other health-related outcomes In all studies except the RA-V study, patients receiving RINVOQ® 15 mg demonstrated greater improvements from baseline in the Physical Component Summary (PCS) score, Mental Component (MCS) score and all eight domains of the Short-Form 36-Item Health Survey (SF-36) at weeks 12 / 14 compared to placebo in combination with cDMARDs or MTX monotherapy.

[0369] Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) in the RA-I, RA-III and RA-IV studies. Improvement in fatigue at week 12 was observed in patients treated with RINVOQ 15 mg compared to placebo-treated patients in combination with cDMARDs or MTX monotherapy.

[0370] 14.2 Psoriatic arthritis The efficacy and safety of RINVOQ® 15 mg once daily was evaluated in two Phase 3 randomized, double-blind, multicenter, placebo-controlled studies in patients aged 18 years or older with moderate to severe active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6 months, at least 3 tender joints and at least 3 swollen joints, and active plaque psoriasis or a history of plaque psoriasis, based on the Classification Criteria for Psoriatic Arthritis (CASPAR). Although alternative doses have been studied, the recommended dose of RINVOQ is 15 mg once daily for psoriatic arthritis.

[0371] The PsA-I study (NCT03104400) was a 24-week study in 1705 patients with moderately to severely active psoriatic arthritis who had an inadequate response or were intolerant to at least one non-biologic DMARD. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily, adalimumab or placebo, alone or in combination with background non-biologic DMARDs. At week 24, all patients randomized to placebo were switched in a blinded manner to RINVOQ 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.

[0372] The PsA-II study (NCT03104374) was a 24-week study in 642 patients with moderately to severely active psoriatic arthritis who had an inadequate response or intolerance to at least one biologic DMARD. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily, or placebo, alone or in combination with background non-biologic DMARDs. At week 24, all patients randomized to placebo were switched in a blinded manner to RINVOQ® 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.

[0373] Clinical response In both studies, patients treated with RINVOQ® 15 mg had significantly more ACR20 responses compared to placebo at week 12 (Table 10, Figure 2). A higher percentage of patients treated with RINVOQ 15 mg had ACR50 and ACR70 responses at week 12 compared to placebo. Treatment with RINVOQ 15 mg improved ACR components compared to placebo at the primary efficacy evaluation time point (Table 11).

[0374] [Table 10]

[0375] [Table 11]

[0376] The percentage of patients achieving an ACR20 response per visit is shown in FIG.

[0377] Treatment with RINVOQ® 15 mg improved dactylitis or enthesitis in patients with pre-existing dactylitis and enthesitis.

[0378] Treatment with RINVOQ® 15 mg improved skin symptoms in patients with PsA. However, RINVOQ® has not been studied and is not indicated for the treatment of plaque psoriasis.

[0379] Physical Function Response In both studies, patients treated with RINVOQ® 15 mg demonstrated significant improvements in physical function from baseline compared with placebo as assessed by the HAQ-DI at week 12 (Table 10). The mean difference (95% CI) from placebo in the change from baseline in the HAQ-DI at week 12 was -0.28 (-0.35, -0.22) in the PsA-I study and -0.21 (-0.30, -0.12) in the PsA-II study.

[0380] The proportion of HAQ-DI responders (HAQ-DI score improvement from baseline of ≥ 0.35) at week 12 in the PsA-I and PsA-II studies was 58% and 45%, respectively, in patients receiving RINVOQ® 15 mg and 33% and 27%, respectively, in patients receiving placebo.

[0381] Radiation Response In the PsA-I study, inhibition of progression of structural damage was assessed radiographically and expressed as change from baseline in the modified total Sharp score (mTSS) and its components, erosion score and joint space narrowing score, at 24 weeks.

[0382] Treatment with RINVOQ® 15 mg inhibited progression of structural joint damage compared to placebo at week 24 (Table 12). Analysis of erosion scores and joint space narrowing scores was consistent with the overall results. The proportion of patients free of radiographic progression (mTSS change ≦0) at week 24 was 93% in patients receiving RINVOQ® 15 mg and 89% in patients receiving placebo.

[0383] [Table 12]

[0384] Other health-related outcomes Health-related quality of life was assessed by the SF-36. In both studies, patients receiving RINVOQ® 15 mg experienced significantly greater improvement from baseline in the Physical Component Summary score compared to placebo at week 12. Greater improvements were also observed in the Mental Component Summary score and all eight domains of the SF-36 compared to placebo.

[0385] Patients receiving RINVOQ® 15 mg showed greater improvement from baseline in fatigue as measured by FACIT-F score at week 12 compared to placebo in both studies.

[0386] Atopic dermatitis The efficacy of RINVOQ® 15 mg and 30 mg once daily was evaluated in three Phase 3, randomized, double-blind, multicenter studies (AD-1, AD-2, AD-3; NCT03569293, NCT03607422, NCT03568318, respectively) in a total of 2584 patients (ages 12 years and older). RINVOQ® was evaluated in 344 pediatric and 2240 adult patients with moderate to severe atopic dermatitis (AD) not adequately controlled by topical medications.

[0387] Disease severity at baseline was defined as a validated Investigator's Global Assessment (vIGA-AD) score ≥3 on a severity scale of 0 to 4 on the Global Assessment of AD, an Eczema Area and Severity Index (EASI) score ≥16, minimal involvement of ≥10% of body surface area (BSA), and a mean weekly worst pruritus numerical rating scale (NRS) score ≥4. Overall, 57% of patients were male and 69% were white. The mean age at baseline was 34 years (range 12-75 years), and 13% of patients were aged 12 to <18 years. At baseline, 49% of patients had a vIGA-AD score of 3 (moderate AD) and 51% of patients had a vIGA-AD score of 4 (severe AD). The mean baseline EASI score was 29, and the mean baseline weekly worst pruritus NRS score was 7. Approximately 52% of patients had prior exposure to systemic AD treatments.

[0388] In all three studies, patients received oral RINVOQ® at 15 mg, 30 mg, or a matching placebo once daily for 16 weeks. In Study AD-3, patients received RINVOQ or placebo in combination with topical corticosteroids (TCS) for 16 weeks.

[0389] All three studies assessed co-primary endpoints of the proportion of patients with at least a 2-point improvement in vIGA-AD score of 0 (clear) or 1 (almost clear) and the proportion of patients with EASI-75 (at least 75% improvement from baseline in EASI score) at week 16. Secondary endpoints included EASI-90 and EASI-100 at week 16 and the proportion of patients with reduced itch (≥4-point improvement from baseline in the Worst Pruritus NRS) at weeks 1, 4, and 16. In the AD-1 and AD-2 studies, the proportion of patients with reduced pain (≥4-point improvement from baseline in the Atopic Dermatitis Symptom Scale (ADerm-SS) Skin Pain NRS) from baseline to week 16 was a secondary endpoint.

[0390] Clinical response Monotherapy studies (AD-1 and AD-2) The results of the RINVOQ® monotherapy studies (AD-1 and AD-2) are shown in Table 13. Figures 3A and 3B show the proportion of patients with a ≧4-point improvement in the Worst Pruritus NRS at weeks 1, 4, and 16 for the AD-1 and AD-2 studies, respectively.

[0391] [Table 13]

[0392] Examination of age, sex, race, weight, and prior systemic treatment with immunosuppressants did not identify differences in response to RINVOQ® between these subgroups in the AD-1 and AD-2 studies.

[0393] TCS combination test (AD-3) Results of the RINVOQ® with TCS study (AD-3) are shown in Table 14. Figure 4 shows the percentage of patients with a ≧4 point improvement in the Worst Pruritus NRS at weeks 1, 4, and 16 for the AD-3 study. Examination of age, sex, race, weight, and prior systemic treatment with immunosuppressants did not identify differences in response to RINVOQ® between these subgroups in the AD-3 study.

[0394] [Table 14]

[0395] Pediatric patient population For pediatric patients aged 12 years and older, efficacy results at week 16 from the RINVOQ® monotherapy studies (AD-1 and AD-2) and the RINVOQ® combination therapy study with TCS (AD-3) are shown in Tables 15 and 16, respectively.

[0396] [Table 15]

[0397] [Table 16]

[0398] Supply method / storage method and handling Supply method RINVOQ® extended-release tablets are supplied as follows: · 15mg: Purple, biconvex oblong, 14 x 8mm in size, with "a15" debossed on one side. 30 tablets per bottle; NDC: 0074-2306-30 · 30mg: Red, biconvex oblong, 14x8mm in size, with “a30” debossed on one side. 30 tablets per bottle; NDC: 0074-2310-30

[0399] Storage and Handling Store between 2°C and 25°C (36°F and 77°F). Store in original bottle to protect from moisture.

[0400] Patient Counseling Information Advise patients to read the FDA-approved patient labeling.

[0401] Serious infections Inform patients that they may be more likely to develop an infection when taking RINVOQ®. Instruct patients to contact their health care provider immediately if they develop any signs or symptoms of an infection during treatment. Advise patients that the risk of herpes zoster, which may be severe, is increased in patients taking RINVOQ®.

[0402] Malignant tumors Inform patients that RINVOQ® may increase the risk of certain cancers and that they should have regular skin tests while using RINVOQ®. Advise patients that they should limit exposure to sunlight and UV light by wearing protective clothing and using a broad-spectrum sunscreen.

[0403] Major adverse cardiovascular events Inform patients that RINVOQ may increase the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. All patients, especially those who are current or former smokers or have other cardiovascular risk factors, should remain vigilant for the development of signs and symptoms of a cardiovascular event.

[0404] thrombosis Inform patients that events of deep vein thrombosis and pulmonary embolism have been reported in clinical trials with RINVOQ. Instruct patients to seek immediate medical attention if they experience any signs or symptoms of DVT or PE.

[0405] Hypersensitivity reactions Advise patients to discontinue RINVOQ and seek immediate medical attention if they experience any signs or symptoms of an allergic reaction.

[0406] Gastrointestinal perforation Inform patients that gastrointestinal perforation has been reported in clinical trials with RINVOQ® and risk factors include use of NSAIDS or a history of diverticulitis. Instruct patients to seek immediate medical attention if they experience new-onset abdominal pain, fever, chills, nausea, or vomiting.

[0407] Retinal detachment Inform patients that retinal detachment has been reported in clinical trials with RINVOQ®. Advise patients to immediately report any sudden changes in vision while receiving RINVOQ® to their healthcare provider.

[0408] Abnormal laboratory test results Inform patients that RINVOQ® may affect certain laboratory tests and that blood tests are necessary before and during treatment with RINVOQ®.

[0409] Vaccination Advise patients to avoid concomitant use of live vaccines with RINVOQ. Instruct patients to inform their healthcare professionals that they are taking RINVOQ before they may receive a vaccination.

[0410] Embryo-fetal toxicity Advise pregnant women and females of reproductive potential that exposure to RINVOQ® during pregnancy may cause fetal harm. Advise women to tell their health care provider if they are pregnant or suspected. Advise females of reproductive potential that they should use effective contraception during treatment and for 4 weeks after the final dose of upadacitinib.

[0411] Breastfeeding Advise women not to breast-feed during treatment with RINVOQ® and for 6 days after the final dose.

[0412] Administration Advise patients not to chew, crush, or split RINVOQ tablets.

[0413] Drug Guide RINVOQ® (RIN-VOKE) extended-release tablets for oral use.What is the most important information I should know about RINVOQ®?RINVOQ® can cause serious side effects, including:

[0414] 1. Severe infection. RINVOQ® is a medicine that affects the immune system. RINVOQ® may weaken the immune system's ability to fight infection. Some people have developed serious infections while taking RINVOQ, including tuberculosis (TB) and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Healthcare providers should test for TB before starting treatment with RINVOQ®. Healthcare providers should monitor patients very closely for signs and symptoms of TB during treatment with RINVOQ®. If you have an infection of any kind, you should not start taking RINVOQ® until your healthcare provider says it is OK. You may be at higher risk of developing shingles (herpes zoster). Before starting RINVOQ®, tell your healthcare provider if: You are treating an infection. ○ You have had an infection that does not go away or keeps coming back. - If you have diabetes, chronic lung disease, HIV, or a weakened immune system. - You have TB or have been in close contact with someone with TB. ○You have shingles (herpes zoster). ○You are currently infected with or have previously been infected with Hepatitis B or C. - You live or have lived in, or have traveled to, certain areas of the country where you are more likely to get certain fungal infections (e.g., the Ohio and Mississippi River valleys and the Southwest). These infections may occur or become more severe when you use RINVOQ. If you are not sure if you have lived in an area where these infections are common, ask your health care provider. Thinking that you have an infectious disease or have symptoms of an infectious disease, such as: Fever, sweats, or chills Muscle pain ○ Cough Shortness of breath Feeling tired ○ Weight loss ○ Your skin is warm, red, or sore, or your body feels tingly. Blood in the phlegm ○ Diarrhea or stomach pain Burning sensation when urinating or urinating more frequently than usual.

[0415] If you experience any symptoms of an infection after starting RINVOQ®, call your healthcare provider immediately. RINVOQ® may increase your chances of getting an infection or worsen any infection you have. If you have a serious infection, your healthcare provider may stop treatment with RINVOQ® until the infection is controlled.

[0416] 2. An increased risk of death in people aged 50 years or older who have at least one heart disease (cardiovascular) risk factor and are taking a class of medications called Janus kinase (JAK) inhibitors. RINVOQ® is a JAK inhibitor drug.

[0417] 3. Cancer and immune system problems. RINVOQ® may increase the risk of certain cancers by changing the way your immune system works. Other cancers, including lymphoma and skin cancer, may occur in people taking RINVOQ. People taking a class of medicines called Janus kinase (JAK) inhibitors are at higher risk of certain cancers, including lymphoma and lung cancer, especially if they are current or former smokers. Tell your health care provider if you have ever had any type of cancer. Follow your health care provider's advice about testing your skin for skin cancer during treatment with RINVOQ®. Limit time in the sun. Avoid using tanning beds or sunlamps. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF 30 or higher) when in the sun. This is especially important for people with very fair skin or a family history of skin cancer.

[0418] 4. People over 50 who have at least one heart disease (cardiovascular) risk factor and are taking medicines in a class called JAK inhibitors are at increased risk of a major cardiovascular event, such as heart attack, stroke, or death, especially if they are current or former smokers.

[0419] Call emergency help right away if you experience any symptoms of a heart attack or stroke while taking RINVOQ, including: Discomfort in the central chest that lasts more than a few minutes or that does not go away or comes back. Severe stiffness, pain, pressure, or heaviness in the chest, throat, neck, or jaw Pain or discomfort in the arms, back, neck, jaw, or stomach Shortness of breath with or without chest discomfort Cold sweat Nausea or vomiting Feeling lightheaded Weakness in one or both parts of the body Slurred speech

[0420] 5. Blood clots (thrombosis). Blood clots in the veins of the legs (deep vein thrombosis, DVT) or in the lungs (pulmonary embolism, PE) and arteries (arterial thrombosis) can occur in some people taking RINVOQ®. This can be life-threatening and may lead to death. Blood clots in the veins of the legs (DVT) and lungs (PE) are more common in people who are 50 years of age or older and have at least one heart (cardiovascular) risk factor who take a class of medicines called Janus kinase (JAK) inhibitors. Tell your healthcare provider if you have had a blood clot in the veins of your legs or lungs in the past. Get medical help right away if you have any signs or symptoms of a blood clot while being treated with RINVOQ®, including: · Swelling Sudden, unexplained chest pain or upper back pain Pain or tenderness in one or both legs Shortness of breath or difficulty breathing

[0421] 6. Allergic reactions. Symptoms that may mean you are having an allergic reaction include rash (hives), difficulty breathing, feeling faint or dizzy, or swelling of the lips, tongue, or throat. Some of these reactions have been serious. If you experience any of these symptoms during treatment with RINVOQ, stop taking RINVOQ and seek emergency medical help immediately.

[0422] 7. Tears (perforation) in the stomach or intestines. Tell your health care provider if you have ever had diverticulitis (inflammation of part of the large intestine) or stomach or intestinal ulcers. Some people taking RINVOQ® may tear their stomach or intestine. This happens most often in people who take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. Get medical help right away if you have stomach-area pain, fever, chills, nausea, or vomiting.

[0423] 8. Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start taking RINVOQ® and while you are taking RINVOQ® to check for the following: Low neutrophil and lymphocyte counts. Neutrophils and lymphocytes are types of white blood cells that help the body fight off infection. Low red blood cell count. Red blood cells carry oxygen. Low red blood cell count means you can become anemic and feel weak and tired. Elevated cholesterol levels. Your health care provider should do blood tests to check your cholesterol levels approximately 12 weeks after you start taking RINVOQ® and as needed. Elevated liver enzymes 。 Liver enzymes help tell you if your liver is functioning properly. Elevated liver enzymes may indicate that your healthcare provider needs to order additional testing on your liver.

[0424] You should not take RINVOQ® if your neutrophil, lymphocyte, or red blood cell counts are too low, or if your liver tests are too high. Your healthcare provider may stop your RINVOQ treatment for a period of time if necessary due to changes in these blood test results. For more information about side effects, see "What are the possible side effects of RINVOQ?"

[0425] What is RINVOQ®? RINVOQ® is a prescription drug and a Janus kinase (JAK) inhibitor. To treat adults with moderate to severe rheumatoid arthritis when one or more drugs called tumor necrosis factor (TNF) blockers have been used and have not worked well or could not be tolerated. To treat adults with active psoriatic arthritis when one or more drugs called tumor necrosis factor (TNF) blockers have been used and have not worked well or could not be tolerated. To treat adults and children 12 years of age and older with moderate to severe eczema (atopic dermatitis) that has not responded to previous treatments and when the eczema is not adequately controlled with other pills or injections, including biologics, or when the use of other pills or injections is not advisable.

[0426] RINVOQ® is safe and effective in children 12 years of age and older weighing at least 88 lbs (40 kg) with atopic dermatitis. It is not known if RINVOQ® is safe and effective in children under 18 years of age with juvenile idiopathic arthritis or psoriatic arthritis. It is not known if RINVOQ® is safe and effective in children under 12 years of age with atopic dermatitis. Do not take RINVOQ® if you are allergic to upadacitinib or any of the ingredients in RINVOQ®. For a complete list of ingredients in RINVOQ®, see the back of this Medication Guide.

[0427] Before taking RINVOQ, tell your healthcare provider about all of your medical conditions, including: See "What is the most important information I should know about RINVOQ®?" You have an infection. - Current or former smoker. - You have had a heart attack, other heart condition, or stroke. - You have a liver disorder. You have kidney problems. - You have unexplained stomach (abdominal) pain, a history of diverticulitis or ulcers in the stomach or intestines, or are taking NSAIDs. Low red or white blood cell count. Have recently been immunized (vaccinated) or are scheduled to be immunized. People taking RINVOQ® should not receive live vaccines. - Are pregnant or planning to become pregnant. Based on animal studies, RINVOQ® may cause harm to an unborn baby. Women who are capable of becoming pregnant: Before starting treatment with RINVOQ®, your healthcare provider should verify your pregnancy status. · Effective birth control should be used to avoid becoming pregnant during treatment with RINVOQ® and for 4 weeks after the last dose of RINVOQ®. · Tell your healthcare provider if you think you may be pregnant or if you become pregnant during treatment with RINVOQ®. If you are taking RINVOQ during pregnancy, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov / medwatch for information about your and your baby's health. - You are breastfeeding or plan to breastfeed. RINVOQ® may pass into breast milk. Patients and their healthcare providers should decide whether to take RINVOQ® and breastfeed. Do not breastfeed during treatment with RINVOQ® and for 6 days after the last dose of RINVOQ®.

[0428] Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RINVOQ® and other medicines may affect each other, causing side effects.

[0429] Tell your healthcare provider especially if you are taking: Medicines for fungal infections (such as ketoconazole, itraconazole, posaconazole, or voriconazole) or clarithromycin (for bacterial infections) (These medicines may increase the amount of RINVOQ in your blood.) Rifampin (for bacterial infections) or phenytoin (for nerve disorders) (These medicines may make RINVOQ less effective.) Medicines that affect the immune system, such as azathioprine and cyclosporine (these medicines may increase the risk of infections).

[0430] If you are not sure if you are taking any of these medicines, ask your health care provider or pharmacist. Know the medicines you are taking. When you get new medicines, keep a list of them and show them to your health care provider and pharmacist.

[0431] How should I take RINVOQ®? Take the following medicines exactly as your healthcare provider tells you to use RINVOQ®: Take RINVOQ once daily, with or without food. Take RINVOQ® tablets whole. Do not split, crush, or chew tablets. If you overdose on RINVOQ®, contact your healthcare provider or Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.

[0432] What are the possible side effects of RINVOQ®? RINVOQ can cause serious side effects, including: See "What is the most important information I should know about RINVOQ®?" The most common side effects of RINVOQ® in people treated for rheumatoid arthritis and psoriatic arthritis include: · Upper respiratory tract infections (colds, sinus infections) Shingles (herpes zoster) Herpes simplex virus infections, including cold sores Bronchitis Nausea Cough Fever Acne The most common side effects of RINVOQ® in people being treated for atopic dermatitis include: · Upper respiratory tract infections (colds, sinus infections) Acne Herpes simplex virus infections, including cold sores Headache Increased blood levels of creatine phosphokinase Cough Allergic reactions Inflammation of hair follicles Nausea · Stomach (abdominal) pain Fever Weight gain Shingles (herpes zoster) Influenza · fatigue · Decrease in the number of white blood cells (neutropenia) Muscle pain Influenza-like illness

[0433] Separation or tearing of the lining at the back of the eye (retinal detachment) has occurred in people with atopic dermatitis who have been treated with RINVOQ®. Call your healthcare provider immediately if you experience any sudden changes in vision during treatment with RINVOQ®.

[0434] These are not all the possible side effects of RINVOQ®. Ask your doctor for advice about side effects. Patients may report side effects to FDA at 1-800-FDA-1088.

[0435] How should I store RINVOQ®? Store RINVOQ® between 36°F and 77°F (2°C and 25°C). Store RINVOQ® in the original bottle to protect it from moisture. Keep RINVOQ(R) and all medicines out of the reach of children.

[0436] General information about the safe and effective use of RINVOQ®. Medicines may be prescribed for purposes other than those listed in the Medication Guide. Do not use RINVOQ® for a condition for which it was not prescribed. Do not give RINVOQ to others, even if they have the same condition as you, as it may harm them. You can ask your pharmacist or health care provider for information about RINVOQ® that is written for health care professionals.

[0437] What are the ingredients in RINVOQ® 15 mg tablets? Active ingredient: Upadacitinib. Inactive ingredients: Colloidal silicon dioxide, ferric oxide, hypromellose, red ferric oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid and titanium dioxide.

[0438] What are the ingredients in RINVOQ 30mg tablets? Active ingredient: Upadacitinib Inactive ingredients: Colloidal silicon dioxide, hypromellose, red iron oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid and titanium dioxide.

[0439] Example 2. Prescribing Information for RINVOQ® Prescribing information highlights These highlights do not contain all the information needed to use RINVOQ® safely and effectively. See full prescribing information for RINVOQ®. RINVOQ® (upadacitinib) extended-release tablets, for oral use. First approved in the U.S.: 2019.

[0440] WARNING: Serious infections, mortality, malignancies, major adverse cardiovascular events (MACE) and thrombosis. See full prescribing information for complete boxed warning.

[0441] There is an increased risk of serious bacterial, fungal, viral and opportunistic infections, including tuberculosis (TB), leading to hospitalization or death. If a serious infection occurs, interrupt treatment with RINVOQ® until the infection is controlled. Test for latent TB before and during therapy; treat latent TB before use. Monitor all patients for active TB during treatment, and further monitor patients with an initial, negative latent TB test.

[0442] In patients with rheumatoid arthritis (RA), another Janus kinase (JAK) inhibitor versus a tumor necrosis factor (TNF) blocker is associated with higher all-cause mortality, including sudden cardiovascular death.

[0443] Malignancies have occurred in patients treated with RINVOQ®. High rates of lymphoma and lung cancer in RA patients with other JAK inhibitors vs. TNF blockers.

[0444] In patients with RA, there is a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with another JAK inhibitor vs. TNF blocker.

[0445] Thrombosis has occurred in patients treated with RINVOQ®. Increased incidence of pulmonary embolism, venous thrombosis, and arterial thrombosis with another JAK inhibitor vs. TNF blocker.

[0446] Indications and Usage Rheumatoid arthritis RINVOQ® is indicated for the treatment of adults with moderate to severe active rheumatoid arthritis who have had an inadequate response to or intolerance to one or more TNF-blocking agents. Limitations of Use: Use of RINVOQ® in combination with other JAK inhibitors, biologic DMARDs, or strong immunosuppressants such as azathioprine and cyclosporine is not recommended.

[0447] Psoriatic arthritis RINVOQ® is indicated for the treatment of adults with active psoriatic arthritis who have had an inadequate response to or intolerance to one or more TNF-blocking agents. Limitations of Use: Use of RINVOQ® in combination with other JAK inhibitors, biologic DMARDs, or strong immunosuppressants such as azathioprine and cyclosporine is not recommended.

[0448] Atopic dermatitis RINVOQ® is indicated for the treatment of adult and pediatric patients 12 years of age and older with refractory moderate to severe atopic dermatitis that is not adequately controlled with other systemic medicinal products, including biologics, or when the use of such therapies is undesirable. Limitations of Use: RINVOQ® is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants.

[0449] ulcerative colitis RINVOQ® is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to or intolerance to one or more TNF-blocking agents. Limitations of Use: RINVOQ® is not recommended for use in combination with other JAK inhibitors, biologic therapies for ulcerative colitis, or other strong immunosuppressants, such as azathioprine and cyclosporine.

[0450] DOSAGE and Administration Prior to treatment, immunizations should be updated and evaluation for active and latent tuberculosis, viral hepatitis, liver function, and pregnancy status should be considered. Absolute lymphocyte count should be 500 cells / mL or higher. / mm 3 Absolute neutrophil count is less than 1000 cells / mm 3 Avoid initiating or discontinue RINVOQ® if blood glucose level is below 18.5 g / dL or hemoglobin level is below 8 g / dL. Initiation of RINVOQ® is not recommended in patients with severe hepatic impairment (Child-Pugh class C).

[0451] Recommended Dosage Rheumatoid arthritis and psoriatic arthritis The recommended dose of RINVOQ® is 15 mg taken once daily.

[0452] Atopic dermatitis Pediatric patients aged 12 years or older weighing at least 40 kg and adults under 65 years of age: Initiate treatment with 15 mg orally once daily. If there is no adequate response, consider increasing the dose to 30 mg orally once daily. -Adults 65 years and older: The recommended dose is 15 mg once daily. Severe renal impairment: The recommended dose is 15 mg once daily.

[0453] ulcerative colitis Adults: The recommended induction dose is 45 mg once daily for 8 weeks. The recommended maintenance dose is 15 mg once daily. A maintenance dose of 30 mg once daily may be considered for patients with refractory, severe, or widespread disease. Discontinue RINVOQ® if the 30 mg dose does not produce an adequate therapeutic response. Use the lowest effective dose needed to maintain a response. See full prescribing information for recommended dosage in patients with renal or hepatic impairment and dosage adjustments due to drug interactions.

[0454] Dosage form and strength Extended release tablets: 15 mg, 30 mg, and 45 mg.

[0455] contraindication Known hypersensitivity to upadacitinib or to any of the excipients in RINVOQ®.

[0456] Warnings and Cautions Serious Infections: Avoid the use of RINVOQ® in patients with active serious infections, including localized infections. Hypersensitivity: Severe hypersensitivity reactions (e.g., anaphylaxis) have been reported. Discontinue administration of RINVOQ® if a severe hypersensitivity reaction occurs. Gastrointestinal (GI) Perforation: Monitor patients at risk for GI perforation and promptly evaluate symptomatic patients. Laboratory Abnormalities: Monitoring is recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Embryo-Fetal Toxicity: RINVOQ® may cause fetal harm based on animal studies. Advise female patients of reproductive potential of the potential risk to the fetus and to use effective contraception. Vaccination: Avoid use of RINVOQ® with live vaccines.

[0457] Adverse Reactions Rheumatoid Arthritis and Psoriatic Arthritis: Adverse reactions (≥1%) were upper respiratory tract infection, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, and acne. Atopic dermatitis: Adverse reactions (≥ 1%) were upper respiratory tract infection, acne, herpes simplex, headache, increased blood creatine phosphokinase, cough, hypersensitivity, folliculitis, nausea, abdominal pain, fever, weight gain, herpes zoster, influenza, fatigue, neutropenia, myalgia, and influenza-like illness. Ulcerative colitis: Adverse reactions (≥5%) reported during induction or maintenance are upper respiratory tract infection, increased blood creatine phosphokinase, acne, neutropenia, elevated liver enzymes, and rash.

[0458] Drug interactions Strong CYP3A4 inhibitors: See full prescribing information for dosage adjustments for patients with atopic dermatitis and ulcerative colitis. Strong CYP3A4 inducers: Coadministration of RINVOQ® with strong CYP3A4 inducers is not recommended.

[0459] Use in Special Populations Lactation: Advise against breast-feeding. Hepatic Impairment: RINVOQ® is not recommended in patients with severe hepatic impairment.

[0460] Full Prescribing Information WARNING: SERIOUS INFECTIONS, MORTALITY, MAJOR ADVERSE CARDIOVASCULAR EVENTS AND THROMBOSIS

[0461] Serious infections Patients treated with RINVOQ® are at high risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking immunosuppressive drugs at the same time, such as methotrexate or corticosteroids. If a serious infection develops, RINVOQ® is discontinued until the infection is controlled.

[0462] Reported infections include: Active tuberculosis, which may manifest as pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before using RINVOQ® and during therapy. Treatment for latent infection should be considered before using RINVOQ®. Invasive fungal infections, including cryptococcosis and pneumocystiosis. Bacterial, viral, including herpes zoster, and other infections caused by opportunistic pathogens.

[0463] The risks and benefits of treatment with RINVOQ® should be carefully considered before initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RINVOQ®, including the possible development of tuberculosis in patients who have tested negative for latent tuberculosis infection before initiating therapy.

[0464] mortality rate In a large randomized postmarketing safety trial comparing another Janus kinase (JAK) inhibitor with a tumor necrosis factor (TNF) blocker in rheumatoid arthritis (RA) patients aged 50 years or older with at least one cardiovascular risk factor, a higher overall mortality rate, including sudden cardiovascular death, was observed with the JAK inhibitor.

[0465] Malignant tumors Lymphomas and other malignancies have been observed in patients treated with RINVOQ®. A higher incidence of malignancies (excluding non-melanoma skin cancer (NMSC)) has been observed in RA patients treated with another JAK inhibitor when compared to TNF blockers. Current or former smokers are at even higher risk.

[0466] Major adverse cardiovascular events In RA patients aged 50 years or older with at least one cardiovascular risk factor treated with other JAK inhibitors, higher rates of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) have been observed when compared with TNF blockers. Current or former smokers are at even higher risk. Discontinue RINVOQ® in patients experiencing a myocardial infarction or stroke.

[0467] thrombosis Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, has occurred in patients treated with JAK inhibitors used to treat inflammatory conditions. Many of these adverse events have been serious, and some have been fatal. A higher incidence of thrombosis has been observed in RA patients aged 50 years or older with at least one cardiovascular risk factor treated with other JAK inhibitors, when compared with TNF blockers. Avoid RINVOQ® in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ® and be promptly evaluated.

[0468] Indications and Usage Rheumatoid arthritis RINVOQ® (upadacitinib) is indicated for the treatment of adults with moderate to severe active rheumatoid arthritis who have had an inadequate response to or intolerance to one or more TNF-blocking agents.

[0469] Limitations of Use: The use of RINVOQ® in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or strong immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

[0470] Psoriatic arthritis RINVOQ® is indicated for the treatment of adults with active psoriatic arthritis who have had an inadequate response to or intolerance to one or more TNF-blocking agents.

[0471] Limitations of Use: Use of RINVOQ® in combination with other JAK inhibitors, biologic DMARDs, or strong immunosuppressants such as azathioprine and cyclosporine is not recommended.

[0472] Atopic dermatitis RINVOQ® is indicated for the treatment of adult and pediatric patients 12 years of age and older with moderate to severe refractory atopic dermatitis that is not adequately controlled with other systemic medicinal products, including biologics, or when the use of such treatments is undesirable.

[0473] Limitations of Use: RINVOQ® is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants.

[0474] ulcerative colitis RINVOQ® is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to or intolerance to one or more TNF-blocking agents.

[0475] Limitations of Use: RINVOQ® is not recommended for use in combination with other JAK inhibitors, biologic therapies for ulcerative colitis, or strong immunosuppressants such as azathioprine and cyclosporine.

[0476] DOSAGE and Administration Recommended evaluations and vaccinations prior to initiating treatment Prior to initiating treatment with RINVOQ®, consider performing the following evaluations: Assessment for active and latent tuberculosis (TB) infection - if positive, treat TB before using RINVOQ®. Screen for viral hepatitis according to clinical guidelines - Initiation of RINVOQ® is not recommended in patients with active hepatitis B or C. Complete blood count - absolute lymphocyte count 500 cells / mm 3 Absolute neutrophil count less than 1000 cells / mm 3 Initiation of RINVOQ® is not recommended for patients with a blood glucose level below 18.5 mg / dL or a hemoglobin level below 8 g / dL. Baseline hepatic function: Initiation of RINVOQ® is not recommended in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy Status: Verify the pregnancy status of women of reproductive potential before initiating pregnancy treatment. Update immunization according to current immunization guidelines

[0477] Important Dosing Instructions RINVOQ® tablets should be taken orally with or without food. RINVOQ® tablets should be taken whole. RINVOQ® should not be split, crushed, or chewed.

[0478] Recommended Dosage for Rheumatoid Arthritis The recommended dose of RINVOQ® is 15 mg taken once daily.

[0479] Dosage recommendations for psoriatic arthritis The recommended dose of RINVOQ® is 15 mg taken once daily.

[0480] Recommended Dosage for Atopic Dermatitis Pediatric patients 12 years of age or older weighing at least 40 kg and adults under 65 years of age: Initiate treatment with 15 mg once daily. If adequate response is not achieved, consider increasing dose to 30 mg once daily. If adequate response is not achieved at the 30 mg dose, discontinue RINVOQ. Use the lowest effective dose needed to maintain response. Adults 65 years and older: The recommended dose is 15 mg once daily.

[0481] Recommended Dosage for Ulcerative Colitis Adult patients: Introduction The recommended induction dose of RINVOQ® is 45 mg once daily for 8 weeks. Adult patients: Maintenance The recommended dose of RINVOQ® for maintenance therapy is 15 mg once daily. A once daily dose of 30 mg may be considered for patients with refractory, severe, or widespread disease. Discontinue RINVOQ® if the 30 mg dose does not result in an adequate therapeutic response. Use the lowest effective dose needed to maintain a response.

[0482] Recommended Dosage in Patients with Renal or Severe Hepatic Impairment Renal dysfunction Rheumatoid and psoriatic arthritis: No dose adjustment is necessary for patients with mild, moderate, or severe renal impairment.

[0483] Atopic dermatitis: Severe renal dysfunction [estimated glomerular filtration rate (eGFR) 15 to <30 mL / min / 1.73 m 2 For patients with cerebrovascular disease, the recommended dose is 15 mg once daily. Mild or moderate renal dysfunction (eGFR ≥ 30 mL / min / 1.73 m2 ), no dosage adjustment is necessary for patients with RINVOQ® is a treatment for patients with end-stage renal disease (eGFR < 15 mL / min / 1.73 m 2 ) is not recommended for use in patients with

[0484] Ulcerative colitis: Severe renal dysfunction (eGFR 15 to <30 mL / min / 1.73 m 2 For patients with: Induction: 30 mg once daily for up to 8 weeks · Maintenance: 15mg once a day Mild or moderate renal dysfunction (eGFR ≥ 30 mL / min / 1.73 m 2 ), no dosage adjustment is necessary for patients with RINVOQ® is a treatment for patients with end-stage renal disease (eGFR < 15 mL / min / 1.73 m 2 ) is not recommended for use in patients with

[0485] Liver dysfunction RINVOQ® is not recommended for use in patients with severe hepatic impairment. Rheumatoid arthritis, psoriatic arthritis and atopic dermatitis: No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Ulcerative colitis: The recommended dosage for patients with mild to moderate hepatic impairment (Child-Pugh classification A or B) is: Induction: 30 mg once daily for up to 8 weeks · Maintenance: 15mg once a day

[0486] Dosage Adjustments Due to Drug Interactions Rheumatoid arthritis, psoriatic arthritis, atopic dermatitis The recommended dose in patients receiving a strong CYP3A4 inhibitor is 15 mg once daily.

[0487] ulcerative colitis Recommended dosage in patients with ulcerative colitis receiving strong CYP3A4 inhibitors: Induction: 30 mg once daily for up to 8 weeks · Maintenance: 15mg once a day

[0488] Dose interruption infectious disease If a patient develops a serious infection, including a serious opportunistic infection, interrupt RINVOQ® treatment until the infection is controlled.

[0489] Abnormal laboratory test results Management of laboratory abnormalities may require interruption of medication, as described in Table 17.

[0490] [Table 17]

[0491] Dosage form and strength Extended release tablets: · 15mg: Purple, biconvex oblong, 14 x 8mm in size, with "a15" debossed on one side. · 30mg: Red, biconvex oblong, 14x8mm in size, with “a30” debossed on one side. · 45mg: Yellow to spotty yellow, biconvex oblong, 14x8mm in size, with “a45” debossed on one side.

[0492] contraindication RINVOQ® is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients.

[0493] Warnings and Cautions Serious infections Serious, sometimes fatal, infections have been reported in patients receiving RINVOQ®. The most frequent serious infections reported with RINVOQ® include pneumonia and cellulitis. Among other opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral / esophageal candidiasis, and cryptococcosis have been reported with RINVOQ®. Avoid use of RINVOQ® in patients with active serious infections, including localized infections.

[0494] Patients with chronic or recurrent infections Patients who have been exposed to tuberculosis Patients with a history of serious infections or opportunistic infections Patients who have lived in or traveled to areas with endemic tuberculosis or endemic mycoses; or Before initiating RINVOQ in patients with underlying conditions that may predispose to infection, consider the risks and benefits of treatment.

[0495] Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ®. If a patient develops a serious or opportunistic infection, discontinue RINVOQ®. Patients who develop a new infection while on treatment with RINVOQ® should undergo prompt and complete diagnostic testing appropriate for immunocompromised patients; appropriate antimicrobial therapy should be initiated and the patient should be closely monitored, and if the patient does not respond to antimicrobial therapy, RINVOQ® should be discontinued. Once the infection is controlled, RINVOQ® can be resumed.

[0496] tuberculosis Prior to administration of RINVOQ®, patients should be evaluated and tested for latent and active tuberculosis (TB) infection. Patients with latent TB should be treated with standard antimycobacterial therapy before initiating RINVOQ®. RINVOQ® should not be administered to patients with active TB. In patients with previously untreated latent or active TB where an appropriate course of treatment cannot be identified, and in patients who test negative for latent TB but have risk factors for TB infection, anti-TB therapy should be considered prior to initiating RINVOQ®. Consultation with a physician with expertise in the treatment of TB is recommended to help determine whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients for the development of signs and symptoms of TB while using RINVOQ®, including patients who have tested negative for latent TB infection prior to initiating therapy.

[0497] Viral reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, was reported in clinical trials of RINVOQ®. The risk of herpes zoster appears to be high in patients treated with RINVOQ® in Japan. If a patient develops herpes zoster, consider temporary interruption of RINVOQ® until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed according to clinical guidelines before initiating and during therapy with RINVOQ®. Patients who tested positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical trials. Patients who tested 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 Phase 3 clinical trials of RINVOQ®. If hepatitis B virus DNA is detected while receiving RINVOQ®, a hepatologist should be consulted.

[0498] mortality rate In another large randomized post-marketing safety study of a JAK inhibitor in RA patients aged 50 years or older with at least one cardiovascular risk factor, a higher overall mortality rate, including sudden cardiovascular death, was observed in patients treated with JAK inhibitors compared with TNF blockers. Consider the benefits and risks for each individual patient before initiating or continuing therapy with RINVOQ®.

[0499] Malignant tumors and lymphoproliferative disorders Malignancies, including lymphoma, were observed in clinical trials of RINVOQ®. In a large randomized post-marketing safety study of another JAK inhibitor in RA patients, the incidence of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed to be higher in patients treated with JAK inhibitors compared to patients treated with TNF blockers. The incidence of lymphoma was observed to be higher in patients treated with JAK inhibitors compared to patients treated with TNF blockers. The incidence of lung cancer was observed to be higher in smokers currently or formerly treated with JAK inhibitors compared to smokers treated with TNF blockers. In this study, current or former smokers had an even higher overall risk of malignancies. Before initiating or continuing therapy with RINVOQ®, consider the benefits and risks for each individual patient, especially those with known malignancies (excluding successfully treated NMSC), those who develop malignancies during treatment, and those who are current or former smokers.

[0500] Nonmelanoma skin cancer NMSC has been reported in patients treated with RINVOQ®. Regular skin examinations are recommended for patients at high risk for skin cancer. Exposure to sunlight and UV rays should be limited by wearing protective clothing and using broad-spectrum sunscreens.

[0501] Major adverse cardiovascular events In another large randomized post-marketing safety trial of a JAK inhibitor in RA patients aged 50 years or older with at least one cardiovascular risk factor, the rate of major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke, was observed to be higher in patients treated with a JAK inhibitor compared with patients treated with a TNF blocker. Current or former smokers were at even higher risk.

[0502] Before initiating or continuing therapy with RINVOQ®, consider the benefits and risks for the individual patient, especially those who are current or former smokers and those with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if such an event occurs. Discontinue RINVOQ® in patients who have experienced a myocardial infarction or stroke.

[0503] thrombosis Thrombosis, including deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, has occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ®. Many of these adverse events have been serious and some have been fatal.

[0504] In a large randomized post-marketing safety study of another JAK inhibitor in RA patients aged 50 years or older with at least one cardiovascular risk factor, a higher incidence of total thrombosis, DVT, and PE was observed compared to patients treated with TNF blockers. If symptoms of thrombosis occur, patients should discontinue RINVOQ® and be promptly evaluated and treated appropriately. Avoid RINVOQ® in patients at risk for increased thrombosis.

[0505] Hypersensitivity reactions In clinical trials, serious hypersensitivity reactions, e.g., anaphylaxis and angioedema, have been reported in patients receiving RINVOQ®. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ® and initiate appropriate therapy.

[0506] Gastrointestinal perforation Gastrointestinal perforation has been reported in clinical trials with RINVOQ®, in which many of the patients with rheumatoid arthritis were receiving background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs).

[0507] Monitor patients treated with RINVOQ® who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Promptly evaluate patients presenting with new-onset abdominal pain for early identification of gastrointestinal perforation.

[0508] Abnormal laboratory test results Neutropenia Treatment with RINVOQ® was associated with a decline in neutropenia (ANC below 1000 cells / mm 3 Neutrophil counts should be assessed at baseline and thereafter according to routine patient management. Patients with low neutrophil counts (i.e., ANC < 1000 cells / mm 3 Avoid initiating RINVOQ and discontinue RINVOQ treatment in patients with pulmonary embolism (less than 18 days after onset of pulmonary embolism).

[0509] Lymphocytopenia ALC is 500 cells / mm 3 Lymphocyte counts less than 500 cells / mm3 have been reported in patients treated with RINVOQ® in clinical trials. Lymphocyte counts should be assessed at baseline and thereafter according to routine patient care. Patients with low lymphocyte counts (i.e., less than 500 cells / mm3) should be monitored for lymphocyte counts. 3 Avoid initiating RINVOQ and discontinue RINVOQ treatment in patients with pulmonary embolism (less than 18 days after onset of pulmonary embolism).

[0510] anemia In clinical trials, declines in hemoglobin levels below 8 g / dL have been reported in patients treated with RINVOQ®. Assess hemoglobin at baseline and thereafter according to routine patient care. Avoid initiating RINVOQ® and discontinue RINVOQ® treatment in patients with low hemoglobin levels (i.e., <8 g / dL).

[0511] 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. Elevations in LDL cholesterol decreased to pretreatment levels in response to statin therapy. The impact of increases in these lipid parameters on cardiovascular morbidity and mortality has not been determined. Evaluate lipid parameters approximately 12 weeks after initiation of treatment and thereafter according to clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for management of hyperlipidemia.

[0512] Elevated liver enzymes Treatment with RINVOQ® was associated with an increased incidence of liver enzyme elevations compared to placebo treatment. Liver enzymes should be assessed at baseline and thereafter according to routine patient care. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If, during routine patient care, an increase in ALT or AST is observed and drug-induced liver injury is suspected, RINVOQ® should be discontinued until this diagnosis has been excluded.

[0513] Embryo-fetal toxicity Based on findings from animal studies, RINVOQ® may cause fetal harm when administered to pregnant women. Upadacitinib has been associated with increased fetal malformations when administered to rats and rabbits during the stage of organogenesis. Verify the pregnancy status of patients of reproductive potential prior to initiating treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with RINVOQ® and for 4 weeks after completing therapy.

[0514] Vaccination Avoid the use of live vaccines during or immediately prior to RINVOQ® therapy. Prior to initiating RINVOQ®, it is recommended that patients be up-to-date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccination, in accordance with current immunization guidelines.

[0515] Adverse Reactions The following clinically significant adverse reactions are described elsewhere in the labeling: Serious infections · Mortality rate Malignant tumors and lymphoproliferative disorders Major adverse cardiovascular events · thrombosis Hypersensitivity reactions · Gastrointestinal perforation Abnormal laboratory test results

[0516] Clinical trial experience Because clinical trials are conducted under a wide variety of conditions, the adverse reaction rates observed in clinical trials of one drug may not be directly comparable to the adverse reaction rates observed in clinical trials of another drug and may not reflect the rates actually observed.

[0517] Adverse Reactions in Patients with Rheumatoid Arthritis A total of 3833 patients with rheumatoid arthritis were treated with upadacitinib in Phase 3 clinical trials, of which 2806 patients were exposed for at least 1 year. Depending on the study design, patients could transition or switch from placebo to RINVOQ® 15 mg or seek relief from active comparator or placebo to RINVOQ® as early as week 12. A total of 2630 patients received at least one dose of RINVOQ® 15 mg, of which 1860 patients were exposed for at least 1 year. In the RA-I, RA-II, RA-III and RA-V studies, 1213 patients received at least one dose of RINVOQ® 15 mg, of which 986 patients were exposed for at least 1 year, and 1203 patients received at least one dose of upadacitinib 30 mg, of which 946 patients were exposed for at least 1 year.

[0518] [Table 18]

[0519] Other adverse reactions reported in <1% of patients in the RINVOQ® 15 mg group and at higher rates in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (including oral herpes), and oral candidiasis. In the Specific Adverse Reactions section, four pooled data sets are presented: Placebo-Controlled Studies: The RA-III, RA-IV, and RA-V studies were combined to represent safety through weeks 12 / 14 for placebo (n=1042) and RINVOQ® 15 mg (n=1035). The RA-III and RA-V studies were combined to represent safety through weeks 12 for placebo (n=390), RINVOQ® 15 mg (n=385), and upadacitinib 30 mg (n=384). The RA-IV study did not include a 30 mg dose, therefore safety data for upadacitinib 30 mg can only be compared to rates for placebo and RINVOQ® 15 mg by pooling the RA-III and RA-V studies. MTX-Controlled Studies: RA-I and RA-II studies were combined to represent safety through weeks 12 / 14 for MTX (n=530), RINVOQ® 15 mg (n=534), and upadacitinib 30 mg (n=529). 12-Month Exposure Dataset: RA-I, II, III, and V studies were combined to represent long-term safety for RINVOQ® 15 mg (n=1213) and upadacitinib 30 mg (n=1203). Exposure-adjusted incidence rates were adjusted by study for all adverse events reported in this section.

[0520] Specific Adverse Reactions infectious disease Placebo-controlled studies: In RA-III, RA-IV, and RA-V, infections were reported in 218 placebo-treated patients (95.7 per 100 patient-years) and 284 RINVOQ® 15 mg-treated patients (127.8 per 100 patient-years). In RA-III and RA-V, infections were reported in 99 placebo-treated patients (136.5 per 100 patient-years), 118 RINVOQ® 15 mg-treated patients (164.5 per 100 patient-years), and 126 upadacitinib 30 mg-treated patients (180.3 per 100 patient-years).

[0521] MTX-controlled studies: Infections were reported in 127 patients treated with MTX monotherapy (119.5 per 100 patient-years), 104 patients treated with RINVOQ® 15 mg monotherapy (91.8 per 100 patient-years), and 128 patients treated with upadacitinib 30 mg monotherapy (115.1 per 100 patient-years).

[0522] 12-month Exposure Dataset: Infections were reported in 615 patients treated with RINVOQ® 15 mg (83.8 per 100 patient-years) and in 674 patients treated with upadacitinib 30 mg (99.7 per 100 patient-years).

[0523] Serious infections Placebo-controlled studies: In RA-III, RA-IV, and RA-V, serious infections were reported in 6 patients receiving placebo (2.3 per 100 patient-years) and 12 patients treated with RINVOQ® 15 mg (4.6 per 100 patient-years). In RA-III and RA-V, serious infections were reported in 1 patient receiving placebo (1.2 per 100 patient-years), 2 patients treated with RINVOQ® 15 mg (2.3 per 100 patient-years), and 7 patients treated with upadacitinib 30 mg (8.2 per 100 patient-years).

[0524] MTX-controlled studies: Serious infections were reported in 2 patients treated with MTX monotherapy (1.6 per 100 patient-years), 3 patients treated with RINVOQ® 15 mg monotherapy (2.4 per 100 patient-years), and 8 patients treated with upadacitinib 30 mg monotherapy (6.4 per 100 patient-years).

[0525] 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.

[0526] The most frequently reported serious infections were pneumonia and cellulitis.

[0527] tuberculosis Placebo- and MTX-controlled studies: During the placebo-controlled period, no active TB cases were reported in the placebo, RINVOQ® 15 mg, and upadacitinib 30 mg groups. During the MTX-controlled period, no active TB cases were reported in the MTX, RINVOQ® 15 mg, and upadacitinib 30 mg monotherapy groups.

[0528] 12-month Exposure Dataset: Active tuberculosis was reported in two patients treated with RINVOQ® 15 mg and one patient treated with upadacitinib 30 mg. Cases of extrapulmonary tuberculosis were reported.

[0529] Opportunistic infections (excluding tuberculosis) Placebo-controlled studies: In RA-III, RA-IV, and RA-V, opportunistic infections were reported in 3 patients receiving placebo (1.2 per 100 patient-years) and 5 patients treated with RINVOQ® 15 mg (1.9 per 100 patient-years). In RA-III and RA-V, opportunistic infections were reported in 1 patient receiving placebo (1.2 per 100 patient-years), 2 patients treated with RINVOQ® 15 mg (2.3 per 100 patient-years), and 6 patients treated with upadacitinib 30 mg (7.1 per 100 patient-years).

[0530] MTX-controlled studies: Opportunistic infections were reported in 1 patient treated with MTX monotherapy (0.8 per 100 patient-years), 0 patients treated with RINVOQ® 15 mg monotherapy, and 4 patients treated with upadacitinib 30 mg monotherapy (3.2 per 100 patient-years).

[0531] 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.

[0532] Malignant tumors Placebo-controlled studies: In RA-III, RA-IV, and RA-V, malignancies excluding NMSC were reported in 1 patient receiving placebo (0.4 per 100 patient-years) and 1 patient treated with RINVOQ® 15 mg (0.4 per 100 patient-years). In RA-III and RA-V, malignancies excluding NMSC were reported in 0 patients receiving placebo, 1 patient treated with RINVOQ® 15 mg (1.1 per 100 patient-years), and 3 patients treated with upadacitinib 30 mg (3.5 per 100 patient-years).

[0533] MTX-controlled studies: 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.

[0534] 12-month Exposure Dataset: Malignancies excluding NMSC were reported in 13 patients treated with RINVOQ® 15 mg (1.2 per 100 patient-years) and 14 patients treated with upadacitinib 30 mg (1.3 per 100 patient-years).

[0535] Gastrointestinal perforation Placebo-Controlled Studies: (Based on medical review) No gastrointestinal perforations were reported in patients receiving placebo, patients treated with RINVOQ® 15 mg, or patients treated with upadacitinib 30 mg.

[0536] MTX-controlled study: No cases of gastrointestinal perforation were reported in the MTX and RINVOQ® 15 mg group through weeks 12 / 14. Two cases of gastrointestinal perforation were observed in the upadacitinib 30 mg group.

[0537] 12-Month Exposure Dataset: Gastrointestinal perforation was reported in 1 patient treated with RINVOQ® 15 mg and 4 patients treated with upadacitinib 30 mg.

[0538] thrombosis Placebo-controlled studies: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in one patient receiving placebo and one patient treated with RINVOQ® 15 mg. In RA-V, venous thrombosis was observed in one patient treated with RINVOQ® 15 mg. No cases of venous thrombosis were observed in RA-III. No cases of arterial thrombosis were observed up to 12 / 14 weeks.

[0539] MTX-Controlled Studies: 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 weeks 12 / 14. 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.

[0540] 12-month Exposure Dataset: Venous thrombotic events were reported in 5 patients treated with RINVOQ® 15 mg (0.5 per 100 patient-years) and 4 patients treated with upadacitinib 30 mg (0.4 per 100 patient-years). Arterial thrombotic events were reported in 0 patients treated with RINVOQ® 15 mg and 2 patients treated with upadacitinib 30 mg (0.2 per 100 patient-years).

[0541] Abnormal laboratory test results Elevated liver transaminases In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), elevations of alanine transaminase (ALT) and aspartate transaminase (AST) ≥ 3x upper limit of normal (ULN) on at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ® 15 mg and 1.5% and 0.7% of patients receiving placebo, respectively, for up to 12 / 14 weeks. In RA-III and RA-V, elevations of ALT and AST ≥ 3x ULN on 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 1.3% and 1.0% of patients receiving placebo, respectively.

[0542] In MTX-controlled studies, elevations in ALT and AST ≥ 3 x ULN on at least one measurement for up to 12 / 14 weeks 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 1.9% and 0.9% of patients treated with MTX, respectively.

[0543] Elevated lipids Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides, and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Increases in LDL and HDL cholesterol peaked by week 8 and plateaued thereafter. In controlled studies, the changes from baseline in lipid parameters in patients treated with RINVOQ® 15 mg and upadacitinib 30 mg, respectively, up to 12 / 14 weeks are summarized below: · Mean LDL cholesterol increased to 14.81 mg / dL and 17.17 mg / dL. HDL cholesterol averages increased to 8.16 mg / dL and 9.01 mg / dL. · The mean LDL / HDL ratio remained stable. · Triglyceride mean values ​​increased to 13.55mg / dL and 14.44mg / dL.

[0544] In placebo-controlled trials (RA-III, RA-IV, and RA-V), dose-related increases in creatine phosphokinase (CPK) levels were observed with background DMARDs for up to 12 / 14 weeks. Elevations in CPK >5xULN were reported in 1.0% of patients in the RINVOQ® 15 mg group and 0.3% of patients in the placebo group over 12 / 14 weeks. Most increases >5xULN were transient and did not require treatment discontinuation. In RA-III and RA-V, increases in CPK >5xULN were observed in 0.3% of patients receiving placebo, 1.6% of patients treated with RINVOQ® 15 mg, and none in patients treated with upadacitinib 30 mg.

[0545] Neutropenia In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), patients had a mean plasma count of 1000 cells / mm3 or higher in at least one measurement for up to 12 / 14 weeks. 3Dose-related decreases in neutrophil counts below 1000 cells occurred in 1.1% of patients in the RINVOQ® 15 mg group and <0.1% of patients in the placebo group. In RA-III and RA-V, neutrophil counts below 1000 cells on at least one measurement were / mm 3 Reductions below ANC occurred in 0.3% of patients receiving placebo, 1.3% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical trials, ANCs below 1000 cells were / mm 3 Treatment was discontinued when the

[0546] Lymphocytopenia In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), patients were randomized to receive at least one of the following treatments for up to 12 / 14 weeks: lymphocyte counts ≥ 500 cells / mL; / mm 3 Dose-related declines below 0.05 occurred in 0.9% of patients in the RINVOQ 15 mg group and 0.7% of patients in the placebo group. In RA-III and RA-V, lymphocyte counts below 500 cells were not observed in at least one measurement. / mm 3 Reductions below 0.5% occurred in 0.5% of patients receiving placebo, 0.5% of patients treated with RINVOQ® 15 mg, and 2.4% of patients treated with upadacitinib 30 mg.

[0547] anemia In placebo-controlled trials with background DMARDs (RA-III, RA-IV, and RA-V), decreases in hemoglobin below 8 g / dL on at least one measurement occurred in <0.1% of patients in both the RINVOQ® 15 mg and placebo groups for up to 12 / 14 weeks. In RA-III and RA-V, decreases in hemoglobin below 8 g / dL on at least one measurement were observed in 0.3% of patients receiving placebo and in none of the patients treated with RINVOQ® 15 mg and upadacitinib 30 mg.

[0548] Adverse Reactions in Patients with Psoriatic Arthritis A total of 1827 patients with psoriatic arthritis were treated with upadacitinib in clinical trials, representing 1639.2 patient-years of exposure, of which 722 patients were exposed to upadacitinib for at least 1 year. In two Phase 3 studies, 907 patients received at least one dose of RINVOQ® 15 mg, of which 359 patients were exposed for at least 1 year. Two placebo-controlled studies were combined (640 patients treated with RINVOQ® 15 mg once daily, 635 patients receiving placebo) to evaluate the safety of RINVOQ® 15 mg compared to placebo up to 24 weeks after initiation of treatment. Overall, the safety profile observed in patients with active psoriatic arthritis treated with RINVOQ® 15 mg was consistent with that observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequency of herpes zoster and herpes simplex was >1% with RINVOQ® 15 mg (1.1% and 1.4%, respectively) and 0.8% and 1.3%, respectively, in the placebo group. Higher incidences of acne and bronchitis were observed in patients treated with RINVOQ® 15 mg (1.3% and 3.9%, respectively) compared with placebo (0.3% and 2.7%, respectively).

[0549] 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 studies 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 (range 12-75 years), and 13% of patients were aged 12-18 years. In these four studies, 2612 patients were treated orally once daily with RINVOQ® 15 mg or 30 mg, with or without 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 which 791 were exposed for at least 1 year, and 1246 patients received RINVOQ® 30 mg, of which 826 were exposed for at least 1 year. The AD-1, AD-2, and AD-4 studies compared the safety of RINVOQ® monotherapy with placebo through 16 weeks. The AD-3 study compared the safety of RINVOQ® + TCS with placebo + TCS through 16 weeks.

[0550] 0 to 16 weeks (AD-1 study to AD-4 study) In the RINVOQ® studies with and without TCS (Studies AD-1, 2, 3, and 4) through week 16, the percentage of patients who discontinued due to adverse reactions in the RINVOQ® 15 mg, 30 mg, and placebo groups was 2.3%, 2.9%, and 3.8%, respectively. Table 19 summarizes adverse reactions occurring at a rate of at least 1% during the first 16 weeks of treatment in the RINVOQ® 15 mg or 30 mg groups.

[0551] [Table 19]

[0552] Other adverse reactions reported in <1% of patients in the RINVOQ® 15 mg and / or 30 mg groups, and more prevalent than placebo, through week 16 included adverse events of anemia, oral candidiasis, pneumonia, and retinal detachment. The safety profile of RINVOQ® through week 52 was generally consistent with the safety profile observed through week 16. Overall, the safety profile observed in patients with AD treated with RINVOQ® was similar to that in patients with RA. Other specific adverse reactions reported in patients with AD include eczema herpeticum / Kaposi's varicelliform eruption.

[0553] Herpetic eczema / Kaposi's varicelliform rash Placebo-controlled period (16 weeks): Eczema herpeticum was reported in 4 patients treated with placebo (1.6 per 100 patient-years), 6 patients treated with RINVOQ® 15 mg (2.2 per 100 patient-years), and 7 patients treated with RINVOQ® 30 mg (2.6 per 100 patient-years).

[0554] 12-month exposure (Weeks 0-52): Eczema herpeticum was reported in 18 patients (1.6 per 100 person-years) treated with RINVOQ® 15 mg and in 17 patients (1.5 per 100 person-years) treated with RINVOQ® 30 mg.

[0555] Adverse Reactions in Patients with Ulcerative Colitis RINVOQ® was studied in patients with moderately to severely active ulcerative colitis for up to 8 weeks 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 for 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.

[0556] Two lead-in studies (UC-1, UC-2) and a dose-finding study (UC-4) enrolled 109 patients, of whom 719 received RINVOQ® 45 mg once daily.

[0557] The maintenance study (UC-3) enrolled 746 patients, of which 250 patients received RINVOQ® 15 mg once daily and 251 patients received RINVOQ® 30 mg once daily.

[0558] Adverse reactions reported in ≥2% of patients in any treatment arm in the induction and maintenance studies are shown in Tables 20 and 21, respectively.

[0559] [Table 20]

[0560] [Table 21]

[0561] The safety profile of RINVOQ® in the long-term extension study was similar to that observed in the placebo-controlled induction and maintenance phases.

[0562] Overall, the safety profile observed in patients with ulcerative colitis treated with RINVOQ® was similar overall to that in patients with RA and without RA.

[0563] Specific Adverse Reactions Serious infections In the lead-in studies: UC-1, UC-2, and UC-4, serious infections were reported in 5 placebo-treated patients (8.4 per 100 patient-years) and 9 RINVOQ® 45 mg-treated patients (8.4 per 100 patient-years) through week 8.

[0564] In the placebo-controlled maintenance study: UC-3, serious infections were reported in 8 patients receiving placebo (6.3 per 100 patient-years), 8 patients treated with RINVOQ® 15 mg (4.5 per 100 patient-years), and 6 patients treated with RINVOQ® 30 mg (3.1 per 100 patient-years) through Week 52.

[0565] Abnormal laboratory test results Elevated liver transaminases In the UC-1, UC-2, and UC-4 studies, elevations in ALT ≥ 3 x ULN on at least one measurement were observed in 1.5% of patients treated with RINVOQ® 45 mg for 8 weeks and in 0% of patients receiving placebo. AST elevations ≥ 3 x ULN occurred in 1.5% of patients treated with RINVOQ® 45 mg and in 0.3% of patients receiving placebo. Elevations in ALT ≥ 5 x ULN occurred in 0.4% of patients treated with RINVOQ® 45 mg and in 0% of patients receiving placebo.

[0566] In UC-3, elevations in ALT ≥ 3x ULN on at least one measurement were observed in 4% of patients treated with RINVOQ 30 mg, 2% of patients treated with RINVOQ 15 mg, and 0.8% of patients receiving placebo during 52 weeks. Elevations in AST ≥ 3x ULN on 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 receiving placebo. Elevations in ALT ≥ 5x ULN were observed in 0.8% of patients treated with 30 mg, 0.4% of patients treated with 15 mg, and 0.4% of patients receiving placebo.

[0567] Overall, the laboratory abnormalities observed in patients with ulcerative colitis treated with RINVOQ® were similar to those described in patients with RA.

[0568] Drug interactions Strong CYP3A4 inhibitor Upadacitinib exposure may be increased when RINVOQ® is coadministered with a strong CYP3A4 inhibitor (e.g., ketoconazole), which may increase the risk of adverse reactions from RINVOQ®. Closely monitor patients for adverse reactions when RINVOQ® 15 mg once daily is coadministered with a strong CYP3A4 inhibitor.

[0569] For patients with atopic dermatitis, coadministration of RINVOQ® 30 mg once daily with strong CYP3A4 inhibitors is not recommended.

[0570] For patients with ulcerative colitis taking a strong CYP3A4 inhibitor, reduce the RINVOQ® induction dose to 30 mg once daily. The recommended maintenance dose is 15 mg once daily.

[0571] Strong CYP3A4 inducers: Upadacitinib exposure is decreased when RINVOQ® is coadministered with strong CYP3A4 inducers (e.g., rifampin), which may reduce the therapeutic efficacy of RINVOQ®. Coadministration of RINVOQ® with strong CYP3A4 inducers is not recommended.

[0572] Use in Special Populations pregnancy Summary of risks Available data from the pharmacovigilance safety database and post-marketing case reports regarding the use of RINVOQ® in pregnant women are insufficient to assess the drug-associated risk of serious birth defects or miscarriage. Based on animal studies, RINVOQ® may cause adverse effects on the developing fetus. Advise reproductive and pregnant patients of the potential risk to the fetus. In animal embryo-fetal development studies, oral administration of upadacitinib to pregnant rats and rabbits at exposures equivalent to or greater than approximately 2 and 17 times the 15 mg dose and 0.9 and 8.5 times the maximum recommended human dose (MRHD) of 30 mg, respectively, resulted in a dose-related increase in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), an increased post-implantation defect (rabbits only), and reduced fetal weight in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib at approximately 0.3 and 2.5 times the 15 mg dose and 0.2 and 1.3 times the MRHD of 30 mg, respectively, during the period of organogenesis.In a pre- and postnatal development study in pregnant female rats, oral upadacitinib administration at an exposure approximately 1.6 times the MRHD of 30 mg did not result in maternal or developmental toxicity (see Data).

[0573] The background risks of serious birth defects and miscarriage in a given population are unknown. All pregnancies have a background risk of birth defects, defects, or other adverse outcomes. In the U.S. population, the estimated background risks of serious birth defects and miscarriage are 2-4% and 15-20%, respectively.

[0574] Clinical considerations Disease-related maternal and / or embryo / fetal risks Published data suggest that in women with rheumatoid arthritis, increased disease activity is associated with an increased risk of developing adverse pregnancy outcomes, including preterm delivery (before 37 weeks of gestation), low birth weight (<2500 g), and short gestational age at birth.

[0575] data Animal Data In an oral embryo-fetal development study, pregnant rats were administered upadacitinib at doses of 5, 25, and 75 mg / kg / day during organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations consisting of humeral deformity and scapular flexion) at exposures approximately 1.0-fold or greater than the MRHD of 30 mg (based on AUC at maternal oral doses of 5 mg / kg / day or greater). Additional skeletal malformations (forelimb / hindlimb flexion and rib / vertebral defects) and reduced fetal weight were observed in the absence of maternal toxicity at exposures approximately 48-fold the MRHD of 30 mg (based on AUC at maternal oral doses of 75 mg / kg / day).

[0576] In a second oral embryo-fetal development study, pregnant rats were administered upadacitinib at doses of 1.5 and 4 mg / kg / day during organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations including humeral and scapular flexion) at exposures approximately 0.9-fold the MRHD of 30 mg (based on AUC at a maternal oral dose of 4 mg / kg / day). No developmental toxicity was observed in rats at exposures approximately 0.2-fold the MRHD of 30 mg (based on AUC at a maternal oral dose of 1.5 mg / kg / day).

[0577] In an oral embryo-fetal development study, pregnant rabbits were administered upadacitinib at doses of 2.5, 10, and 25 mg / kg / day during organogenesis from day 7 to day 19 of gestation. Embryonic lethality, reduced fetal weight, and cardiovascular malformations were observed in the presence of maternal toxicity at exposures approximately 8.5-fold higher than the MRHD of 30 mg (based on AUC at a maternal oral dose of 25 mg / kg / day). Embryonic lethality consisted of increased post-implantation losses due to increased incidence of total and early resorptions. Developmental toxicity was not observed in rabbits at exposures approximately 1.3-fold higher than the MRHD of 30 mg (based on AUC at a maternal oral dose of 10 mg / kg / day).

[0578] In a pre- and postnatal oral developmental study, pregnant female rats were administered 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 the mothers or pups, respectively, at exposures approximately 1.6-fold the MRHD of 30 mg (based on AUC at a maternal oral dose of 10 mg / kg / day).

[0579] Breastfeeding Summary of risks There are no data regarding the presence of upadacitinib in human milk, its effects on breast-fed infants, or its effects on breast milk production. Available pharmacodynamic / toxicological data in animals indicate excretion of upadacitinib in milk. When a drug is present in animal milk, it may be present in human milk. Advise patients that breast-feeding is not recommended during treatment with RINVOQ® and for 6 days (approximately 10 half-lives) after the final dose due to the potential for serious adverse reactions in breast-fed infants.

[0580] data Lactating female Sprague-Dawley rats were administered a single oral dose of radiolabeled upadacitinib at 10 mg / kg on postpartum days 7-8. Drug exposure was measured using the AUC 0-t Based on the values, approximately 30-fold more was found in milk than in maternal plasma. Approximately 97% of the drug-related substances in milk were the parent drug.

[0581] Women and men of reproductive potential Pregnancy test Verify pregnancy status in females of reproductive potential prior to initiating treatment with RINVOQ®.

[0582] contraception woman Based on animal studies, upadacitinib can cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with RINVOQ® and for 4 weeks after the final dose.

[0583] Pediatric Use Juvenile idiopathic arthritis and psoriatic arthritis The safety and effectiveness of RINVOQ® in pediatric patients with juvenile idiopathic arthritis and psoriatic arthritis have not been established.

[0584] Atopic dermatitis The safety and efficacy of RINVOQ® in pediatric patients aged 12 years or older weighing at least 40 kg with atopic dermatitis has been established. A total of 344 pediatric patients aged 12-17 years with moderate to severe atopic dermatitis were randomized into three studies (AD-1, AD-2, and AD-3) to receive either RINVOQ® 15 mg (N=114) or 30 mg (N=114) or a matching dose of placebo (N=116) as monotherapy or in combination with topical corticosteroids. Efficacy was consistent between pediatric and adult patients. The adverse reaction profile in pediatric patients was similar to that in adults. The safety and efficacy of RINVOQ® in pediatric patients less than 12 years old with atopic dermatitis has not been established.

[0585] ulcerative colitis The safety and effectiveness of RINVOQ® in pediatric patients with ulcerative colitis has not been established.

[0586] Use in the elderly Rheumatoid arthritis and psoriatic arthritis Of 4381 patients treated in five clinical trials, a total of 906 rheumatoid arthritis patients were 65 years of age or older, including 146 patients aged 75 years or older. Of 1827 patients treated in two psoriatic arthritis Phase 3 clinical trials, a total of 274 patients were 65 years of age or older, including 34 patients aged 75 years or older. Efficacy differences were observed between these patients and younger patients, although patients aged 65 years or older had a higher incidence of overall adverse events, including serious infections.

[0587] Atopic dermatitis Of 2583 patients treated in three Phase 3 clinical trials, a total of 120 patients with atopic dermatitis were aged 65 years or older, including 6 patients aged 75 years or older. Efficacy differences were observed between these patients and younger patients, but in the long-term treatment trials, there was a higher incidence of serious infections and malignancies in patients aged 65 years or older in the 30 mg dose group.

[0588] ulcerative colitis Of 1097 patients treated in controlled clinical trials, a total of 95 patients with ulcerative colitis were aged 65 or older. Clinical trials of RINVOQ® did not include sufficient numbers of patients with ulcerative colitis aged 65 or older to determine whether they respond differently than younger adult patients.

[0589] Renal dysfunction For patients with rheumatoid arthritis and psoriatic arthritis, dose adjustments should be minor (eGFR 60 to <90 mL / min / 1.73 m 2 ), moderate (eGFR30~<60mL / min / 1.73m 2 ), or severe (eGFR 15 to <30 mL / min / 1.73 m 2 ) is not required in patients with renal impairment.

[0590] For patients with atopic dermatitis, the maximum recommended dose is 15 mg once daily for patients with severe renal impairment. No dose adjustment is required in patients with mild or moderate renal impairment.

[0591] For patients with ulcerative colitis, the recommended dose for severe renal impairment is 30 mg once daily for induction (up to 16 weeks) and 15 mg once daily for maintenance. No dose adjustment is required in patients with mild or moderate renal impairment.

[0592] RINVOQ® is a treatment for patients with end-stage renal disease (eGFR < 15 mL / min / 1.73 m 2It has not been studied in patients with end-stage renal disease and atopic dermatitis or ulcerative colitis.

[0593] Liver dysfunction The use of RINVOQ® has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and therefore is not recommended for use in patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis or ulcerative colitis.

[0594] For patients with rheumatoid arthritis, psoriatic arthritis, and atopic dermatitis, dosage adjustments are not required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

[0595] For patients with ulcerative colitis, the recommended dose for mild to moderate hepatic impairment is 30 mg once daily for induction and 15 mg once daily for maintenance.

[0596] explanation RINVOQ® contains upadacitinib, a JAK inhibitor. Upadacitinib has the chemical name: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1). The strength of upadacitinib is based on anhydrous upadacitinib. The solubility of upadacitinib in water is 38-0.2 mg / mL at 37°C in the pH range of 2-9. Upadacitinib has a molecular weight of 389.38 g / mol and a molecular formula of C 17 H 19 F3N6O 1 / 2H2O. The chemical structure of upadacitinib is:

[0597] [ka] It is.

[0598] RINVOQ® 15 mg extended-release tablets for oral are purple, biconvex, oblong, measuring 14×8 mm with "a15" debossed on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, triferric oxide, hypromellose, red ferric oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid, and titanium dioxide.

[0599] RINVOQ® 30 mg extended-release tablets for oral administration are red, biconvex, oblong, measuring 14×8 mm, with "a30" debossed on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, red iron oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid, and titanium dioxide.

[0600] RINVOQ® 45 mg extended-release tablets for oral administration are yellow to mottled yellow in color, biconvex oblong in shape, measuring 14×8 mm with "a45" debossed on one side. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, yellow ferric oxide, red ferric oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid, and titanium dioxide.

[0601] Clinical Pharmacology Mechanism of action Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit signals resulting from cytokine or growth factor-receptor interactions on the cell membrane to affect cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which regulate intracellular activities, including gene expression. Upadacitinib regulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

[0602] JAK enzymes mediate cytokine signaling through their pairings (e.g., JAK1 / JAK2, JAK1 / JAK3, JAK1 / TYK2, JAK2 / JAK2, JAK2 / TYK2). In cell-free isolated enzyme assays, upadacitinib was more potent at inhibiting JAK1 and JAK2 than JAK3 and TYK2. In human white blood cell assays, upadacitinib inhibited cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1 / JAK3 more potently than STAT phosphorylation mediated by JAK2 / JAK2. However, the relevance of inhibition of specific JAK enzymes to therapeutic efficacy is currently unknown.

[0603] Pharmacodynamics Inhibition of IL-6-induced STAT3 and IL-7-induced STAT5 phosphorylation In healthy volunteers, administration of upadacitinib (immediate release formulation) dose- and concentration-dependently inhibited IL-6 (JAK1 / JAK2)-induced STAT3 and IL-7 (JAK1 / JAK3)-induced STAT5 phosphorylation in whole blood, with maximal inhibition observed 1 hour after dosing and returning to near baseline by the end of the dosing interval.

[0604] Lymphocytes In patients with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline to week 36, which gradually returned to or near baseline levels with continued treatment.

[0605] Immunoglobulins In patients with rheumatoid arthritis, small decreases from baseline in mean IgG and IgM levels were observed with upadacitinib treatment during the control period, although mean values ​​at baseline and all visits were within normal reference ranges.

[0606] Cardiac Electrophysiology At mean exposures 2.5 times the maximum therapeutic dose of 45 mg once daily, there were no clinically relevant effects on the QTc interval.

[0607] Pharmacokinetics Upadacitinib plasma exposure is dose-proportional across the therapeutic dose range. In healthy subjects, single doses of RINVOQ 15 mg, 30 mg, and 45 mg administered under fasting conditions resulted in mean C max were 31.6 ng / mL, 71.8 ng / mL, and 90.7 ng / mL, respectively, and the mean AUC inf The plasma concentrations were 265 ng·h / mL, 543 ng·h / mL, and 752 ng·h / mL, respectively. Steady-state plasma concentrations were achieved within four days, with minimal accumulation following once-daily dosing. The pharmacokinetics of upadacitinib are comparable in patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ulcerative colitis.

[0608] absorption Following oral administration of the upadacitinib extended-release formulation, upadacitinib max Median absorption time is 2-4 hours.

[0609] Coadministration of a high-fat / high-calorie meal with upadacitinib had no clinically relevant effect on upadacitinib exposure (AUC inf is 29%, C max (In patients with type 2 diabetes, the mean mean mean increased by 39% to 60%). In clinical trials, upadacitinib was administered without regard to food.

[0610] distribution Upadacitinib is 52% bound to plasma proteins. Upadacitinib distributes similarly between plasma and blood cellular components with a blood-to-plasma ratio of 1.0.

[0611] discharge metabolism Metabolism of upadacitinib is primarily mediated by CYP3A4 with a possible minor contribution from CYP2D6. The pharmacological activity of upadacitinib is attributable to the parent molecule. In human radiolabeling studies, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma, and the major metabolite detected (a product of mono-oxidation followed by glucuronidation) accounted for 13% of the total radioactivity in plasma. No active metabolites have been identified for upadacitinib.

[0612] Excretion Following administration of a single dose of [14C]-upadacitinib immediate-release solution, upadacitinib was primarily excreted in the urine (24%) and feces (38%) as unchanged parent drug. Approximately 34% of the upadacitinib dose was excreted as metabolites. The mean terminal elimination half-life of upadacitinib ranged from 8 to 14 hours.

[0613] Specific populations Weight, gender and race Weight, sex, race, ethnicity, and race had no clinically relevant effects on upadacitinib exposure.

[0614] Pediatric patients No significant differences in upadacitinib systemic exposure were observed in pediatric patients 12 years of age and older with atopic dermatitis weighing at least 40 kg compared to adults.

[0615] Elderly patients No clinically meaningful differences in the pharmacokinetics of upadacitinib were observed in elderly patients (≥ 65 years) compared with younger adult patients.

[0616] Patients with renal dysfunction Mean AUC of upadacitinib following administration of a single dose of 15 mg upadacitinib inf Subjects with normal renal function (eGFR ≥ 90 mL / min / 1.73 m 2 ), compared with mild (eGFR 60 to <90 mL / min / 1.73 m 2 ), moderate (eGFR30~<60mL / min / 1.73m 2) and severe (eGFR 15 to <30 mL / min / 1.73 m 2 ) were 18%, 33% and 44% higher in patients with renal impairment, respectively. max were similar between patients with normal and impaired renal function. In patients receiving upadacitinib 15 mg, 30 mg, or 45 mg once daily, mild to moderate renal impairment is not expected to have a clinically relevant effect on upadacitinib exposure.

[0617] Patients with liver dysfunction Mean AUC of upadacitinib following administration of a single dose of 15 mg upadacitinib inf was 28% and 24% higher in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared with subjects with normal hepatic function. max was unchanged in patients with mild hepatic impairment and 43% higher in subjects with moderate hepatic impairment compared with patients with normal liver function. Upadacitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

[0618] Drug interaction studies Other drugs may affect the pharmacokinetics of upadacitinib Upadacitinib is metabolized in vitro by CYP3A4 with a minor contribution from CYP2D6. The effect of concomitant medications on upadacitinib plasma exposure is shown in Table 22.

[0619] [Table 22]

[0620] pH-modifying medicinal products (e.g., antacids or proton pump inhibitors) are not expected to affect the plasma exposure of upadacitinib based on in vitro assessments and population pharmacokinetic analysis. CYP2D6 metabolic phenotype had no effect on the pharmacokinetics of upadacitinib (based on population pharmacokinetic analysis), indicating that CYP2D6 inhibitors have no clinically relevant effects on upadacitinib exposure.

[0621] Potential for upadacitinib to affect the pharmacokinetics of other drugs In vitro studies have shown that upadacitinib does not inhibit or induce the activity of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at clinically relevant concentrations. In vitro studies have shown that upadacitinib does not inhibit the transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations.

[0622] Clinical trials have demonstrated that upadacitinib has no clinically relevant effects on the pharmacokinetics of concomitant medications. After once-daily administration of 30 mg and 45 mg upadacitinib, the effects on each CYP enzyme (CYP1A2, CYP3A, CYP2C9, and CYP2C19) were similar between the two doses, except for the effect on CYP2D6. Weak induction of CYP3A4 was observed after once-daily administration of 30 mg and 45 mg upadacitinib. Weak inhibition of CYP2D6 was observed with upadacitinib 45 mg but not with 30 mg. A summary of results from clinical trials evaluating the effects of upadacitinib on other drugs is shown in Table 23.

[0623] [Table 23]

[0624] 13 Nonclinical Toxicology 13.1 Carcinogenicity, Mutagenicity and Impairment of Reproductive Potential Carcinogenesis The carcinogenic potential of upadacitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats treated with upadacitinib at oral doses of up to 15 mg / kg / day or 20 mg / kg / day, respectively (approximately 2.4- and 6.0-fold the MRHD of 30 mg, based on AUC, respectively) for up to 101 weeks. No evidence of tumorigenicity was observed in male or female Tg.rasH2 mice treated with upadacitinib orally at 20 mg / kg / day for 26 weeks.

[0625] Mutagenicity Upadacitinib has been tested in the following genotoxicity assays, with negative results: in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay.

[0626] Reproductive disorders Upadacitinib had no effect on fertility in male or female rats at oral doses of up to 50 mg / kg / day in males and 75 mg / kg / day in females (approximately 24-fold the MRHD of 30 mg in males and 48-fold the MRHD of 30 mg in females, based on AUC). However, maintenance of pregnancy was adversely affected at oral doses of 25 mg / kg / day and 75 mg / kg / day based on dose-related findings of increased post-implantation losses (increased resorptions) and reduced mean number of viable fetuses per litter (approximately 13-fold and 48-fold the AUC of the MRHD of 30 mg, respectively). The number of viable fetuses was not affected in female rats receiving upadacitinib orally at 5 mg / kg / day and mated to males receiving the same dose (approximately 1.0-fold the AUC of the MRHD of 30 mg).

[0627] Clinical Trials Rheumatoid arthritis The efficacy and safety of RINVOQ® 15 mg once daily was evaluated in five phase 3, randomized, double-blind, multicenter studies in patients with moderately to severely active rheumatoid arthritis fulfilling the ACR / EULAR 2010 classification criteria. Patients aged 18 years or older were eligible to participate. The presence of at least six tender and six swollen joints, and evidence of systemic inflammation based on elevated hsCRP, was required at baseline. The recommended dose of RINVOQ® is 15 mg once daily, although other doses have been studied.

[0628] The RA-I study (NCT02706873) was a 24-week monotherapy study in 947 patients with moderately to severely active rheumatoid arthritis naïve to methotrexate (MTX). Patients received RINVOQ® 15 mg or upadacitinib 30 mg orally once daily or MTX as monotherapy. At week 26, patients unresponsive to upadacitinib could seek salvage with additional MTX and patients unresponsive to MTX could seek salvage with additional blinded RINVOQ® 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients achieving an ACR50 response at week 12. Primary secondary endpoints included Disease Activity Score (DAS28-CRP) ≤ 3.2 at week 12, DAS28-CRP < 2.6 at week 24, change from baseline in HAQ-DI at week 12, and change from baseline in van der Heijde-modified Total Sharpe Score (mTSS) at week 24.

[0629] RA-II (NCT02706951) was a 14-week monotherapy study in 648 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to MTX. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once-daily monotherapy or continued stable MTX monotherapy. At week 14, patients randomized to the MTX group were advanced to RINVOQ® 15 mg or upadacitinib 30 mg once-daily monotherapy in a blinded manner based on the allocation pre-determined at baseline. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 14. Key secondary endpoints included DAS28-CRP≦3.2, DAS28-CRP<2.6, and change from baseline in HAQ-DI at week 14.

[0630] RA-III (NCT02675426) was a 12-week study in 661 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARDs). Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily or placebo in addition to background cDMARD therapy. At week 12, patients randomized to placebo were advanced to RINVOQ® 15 mg or upadacitinib 30 mg once daily in a blinded manner based on the allocation pre-determined at baseline. The primary endpoint was the proportion of patients achieving an ACR20 response at week 12. Key secondary endpoints included DAS28-CRP≦3.2, DAS28-CRP<2.6, and change from baseline in HAQ-DI at week 12.

[0631] The RA-IV study (NCT02629159) was a 48-week study in 1629 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to MTX. Patients received RINVOQ® 15 mg once daily, an active comparator, or a placebo in addition to the MTX backbone. Beginning at week 14, patients not responding to RINVOQ® 15 mg could be rescued in a blinded manner with an active comparator, and patients not responding to either the active comparator or the placebo could be rescued in a blinded manner with RINVOQ® 15 mg. At week 26, all patients randomized to placebo were switched to RINVOQ® 15 mg once daily in a blinded manner. The primary endpoint was the proportion of patients vs. placebo who achieved an ACR20 response at week 12. Key secondary endpoints versus placebo included DAS28-CRP≦3.2, DAS28-CRP<2.6, change from baseline in HAQ-DI at week 12, and change from baseline in mTSS at week 26.

[0632] The RA-V study (NCT02706847) was a 12-week study in 499 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to biologic DMARDs. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily or placebo in addition to background cDMARD therapy. At week 12, patients randomized to placebo were advanced to RINVOQ® 15 mg or upadacitinib 30 mg once daily in a blinded manner based on the allocation pre-determined at baseline. The primary endpoint was the proportion of patients achieving an ACR20 response at week 12. Key secondary endpoints included DAS28-CRP≦3.2 and change from baseline in HAQ-DI at week 12.

[0633] Clinical response The percentage of patients treated with RINVOQ® who achieved ACR20, ACR50 and ACR70 responses, as well as DAS28 (CRP) < 2.6 in all studies is shown in Table 24. Patients treated with RINVOQ® 15mg alone or in combination with cDMARDs achieved higher ACR response rates at the primary efficacy evaluation time point compared to MTX monotherapy or placebo, respectively (Table 24). The visit-by-visit proportion of patients who achieved ACR20 response in Study IV is shown in Figure 1. Higher ACR20 response rates were observed with RINVOQ® 15mg vs. placebo at 1 week in the RA-III and RA-V studies. Treatment with RINVOQ® 15mg alone or in combination with cDMARDs resulted in greater improvements in ACR components compared to MTX or placebo at the primary efficacy evaluation time point (Table 25).

[0634] [Table 24]

[0635] [Table 25] TIFF2025502266000029.tif114162

[0636] In RA-I and RA-IV, a higher percentage of patients treated with RINVOQ® 15 mg alone or in combination with MTX achieved a DAS28-CRP < 2.6 at the primary efficacy evaluation time point compared with MTX or placebo (Table 26).

[0637] [Table 26]

[0638] Radiation Response Inhibition of progression of structural joint damage was assessed using the modified total Sharp score (mTSS) and its components erosion score and joint space narrowing score at week 26 in Study RA-IV and at week 24 in Study RA-I. The proportion of patients with radiographic freedom from progression (mTSS change from baseline ≤ 0) was also assessed.

[0639] In the RA-IV study, treatment with RINVOQ® 15 mg inhibited the progression of structural joint damage compared to placebo in combination with cDMARDs at week 26 (Table 27). Analysis of erosion scores and joint space narrowing scores was consistent with the overall results.

[0640] In the placebo + MTX group, 76% of patients were free of radiographic progression at 26 weeks compared with 83% of patients treated with RINVOQ® 15 mg.

[0641] In the RA-I study, treatment with RINVOQ® 15 mg monotherapy inhibited the progression of structural joint damage at week 24 compared to MTX monotherapy (Table 27). Analysis of erosion scores and joint space narrowing scores was consistent with the overall results.

[0642] In the MTX monotherapy group, 78% of patients were free of radiographic progression at 24 weeks compared with 87% of patients treated with RINVOQ® 15 mg monotherapy.

[0643] [Table 27]

[0644] Physical Function Response Treatment with RINVOQ® 15 mg alone or in combination with cDMARDs was associated with greater improvements in physical function at weeks 12 / 14 compared to all comparators as measured by HAQ-DI.

[0645] Other health-related outcomes In all studies except the RA-V study, patients receiving RINVOQ® 15 mg demonstrated greater improvements from baseline in the Physical Component Summary (PCS) score, Mental Component (MCS) score and all eight domains of the Short-Form 36-Item Health Survey (SF-36) at weeks 12 / 14 compared to placebo in combination with cDMARDs or MTX monotherapy.

[0646] Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) in the RA-I, RA-III and RA-IV studies. Improvement in fatigue at week 12 was observed in patients treated with RINVOQ® 15 mg compared to patients receiving placebo in combination with cDMARDs or MTX monotherapy.

[0647] Psoriatic arthritis The efficacy and safety of RINVOQ® 15 mg once daily was evaluated in two phase 3 randomized, double-blind, multicenter, placebo-controlled studies in patients aged 18 years or older with moderate to severe active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6 months, at least 3 tender joints and at least 3 swollen joints, and active plaque psoriasis or a history of plaque psoriasis, based on the Classification Criteria for Psoriatic Arthritis (CASPAR). Although alternative doses have been studied, the recommended dose of RINVOQ® is 15 mg once daily for psoriatic arthritis.

[0648] The PsA-I study (NCT03104400) was a 24-week study in 1705 patients with moderately to severely active psoriatic arthritis who had an inadequate response or were intolerant to at least one non-biologic DMARD. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily, adalimumab or placebo, alone or in combination with background non-biologic DMARDs. At week 24, all patients randomized to placebo were switched in a blinded manner to RINVOQ® 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.

[0649] The PsA-II study (NCT03104374) was a 24-week study in 642 patients with moderately to severely active psoriatic arthritis who had an inadequate response or intolerance to at least one biologic DMARD. Patients received RINVOQ® 15 mg or upadacitinib 30 mg once daily, or placebo, alone or in combination with background non-biologic DMARDs. At week 24, all patients randomized to placebo were switched in a blinded manner to RINVOQ® 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.

[0650] Clinical response In both studies, patients treated with RINVOQ® 15 mg had a significantly higher ACR20 response compared to placebo at week 12 (Table 28, Figure 2). A higher percentage of patients treated with RINVOQ® 15 mg had ACR50 and ACR70 responses compared to placebo at week 12. Treatment with RINVOQ® 15 mg improved ACR components compared to placebo at the primary efficacy evaluation time point (Table 29).

[0651] [Table 28]

[0652] [Table 29]

[0653] The percentage of patients achieving an ACR20 response per visit is shown in FIG.

[0654] Treatment with RINVOQ® 15 mg improved dactylitis or enthesitis in patients with pre-existing dactylitis and enthesitis.

[0655] Treatment with RINVOQ® 15 mg improved skin symptoms in patients with PsA. However, RINVOQ® has not been studied and is not indicated for the treatment of plaque psoriasis.

[0656] Physical Function Response In both studies, patients treated with RINVOQ® 15 mg demonstrated significant improvements in physical function from baseline compared with placebo as assessed by the HAQ-DI at Week 12 (Table 26). The mean difference (95% CI) from placebo in the change from baseline in the HAQ-DI at Week 12 was -0.28 (-0.35, -0.22) in the PsA-I study and -0.21 (-0.30, -0.12) in the PsA-II study.

[0657] The proportion of HAQ-DI responders (HAQ-DI score improvement from baseline of ≥ 0.35) at week 12 in the PsA-I and PsA-II studies was 58% and 45%, respectively, in patients receiving RINVOQ® 15 mg and 33% and 27%, respectively, in patients receiving placebo.

[0658] Radiation Response In the PsA-I study, inhibition of progression of structural damage was assessed radiographically and expressed as change from baseline in the modified total Sharp score (mTSS) and its components, erosion score and joint space narrowing score, at 24 weeks.

[0659] Treatment with RINVOQ® 15 mg inhibited the progression of structural joint damage compared to placebo at week 24 (Table 28). Analysis of erosion scores and joint space narrowing scores was consistent with the overall results. The proportion of patients free of radiographic progression (mTSS change ≦0) at week 24 was 93% in patients receiving RINVOQ® 15 mg and 89% in patients receiving placebo.

[0660] [Table 30]

[0661] Other health-related outcomes Health-related quality of life was assessed by the SF-36. In both studies, patients receiving RINVOQ® 15 mg experienced significantly greater improvement from baseline in the Physical Component Summary score compared to placebo at week 12. Greater improvements were also observed in the Mental Component Summary score and all eight domains of the SF-36 compared to placebo.

[0662] Patients receiving RINVOQ® 15 mg showed greater improvement from baseline in fatigue as measured by FACIT-F score at week 12 compared to placebo in both studies.

[0663] Atopic dermatitis The efficacy of RINVOQ® 15 mg and 30 mg once daily was evaluated in three Phase 3, randomized, double-blind, multicenter studies (AD-1, AD-2, AD-3; NCT03569293, NCT03607422, NCT03568318, respectively) in a total of 2584 patients (ages 12 years and older). RINVOQ® was evaluated in 344 pediatric and 2240 adult patients with moderate to severe atopic dermatitis (AD) not adequately controlled by topical medications.

[0664] Disease severity at baseline was defined as a validated Investigator's Global Assessment (vIGA-AD) score ≥3 on a severity scale of 0 to 4 on the Global Assessment of AD, an Eczema Area and Severity Index (EASI) score ≥16, minimal involvement of ≥10...

Claims

[Claim 1] 1. A method of treating a patient receiving a strong CYP3A4 inhibitor concomitantly with upadacitinib, comprising: reducing the recommended daily dose of upadacitinib from 45 mg to 30 mg while the patient is receiving a strong CYP3A4 inhibitor; reducing the recommended daily dose of upadacitinib from 30 mg to 15 mg while the patient is receiving a strong CYP3A4 inhibitor; and maintaining the recommended daily dose of upadacitinib at 15 mg for the period the patient is receiving a strong CYP3A4 inhibitor; A method comprising:

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