1.1 Rheumatoid Arthritis

RINVOQ® is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

● Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine.

1.2 Psoriatic Arthritis

RINVOQ is indicated for the treatment of adults with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

● Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

1.3 Atopic Dermatitis

RINVOQ is indicated for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable.

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

1.4 Ulcerative Colitis

RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers.

● Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for ulcerative colitis, or with potent immunosuppressants such as azathioprine and cyclosporine.

1.5 Crohn’s Disease

RINVOQ is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response or intolerance to one or more TNF blockers.

● Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for Crohn’s disease, or with potent immunosuppressants such as azathioprine and cyclosporine.

1.6 Ankylosing Spondylitis

RINVOQ is indicated for the treatment of adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blockers.

● Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

1.7 Non-radiographic Axial Spondyloarthritis

RINVOQ is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation who have had an inadequate response or intolerance to TNF blocker therapy.

● Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

2.1 Recommended Evaluations and Immunizations Prior to Treatment Initiation

Prior to RINVOQ treatment initiation, consider performing the following evaluations:

● Active and latent tuberculosis (TB) infection evaluation - If positive, treat for TB prior to RINVOQ use [see Warnings and Precautions (5.1)].

● Viral hepatitis screening in accordance with clinical guidelines - RINVOQ initiation is not recommended in patients with active hepatitis B or hepatitis C [see Warnings and Precautions (5.1)].

● A complete blood count - RINVOQ initiation is not recommended in patients with an absolute lymphocyte count less than 500 cells/mm3, absolute neutrophil count less than 1000 cells/mm3, or hemoglobin level less than 8 g/dL [see Dosage and Administration (2.12) and Warnings and Precautions (5.8)].

● Baseline hepatic function: RINVOQ initiation is not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

● Pregnancy Status: Verify the pregnancy status of females of reproductive potential prior to starting treatment [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1, 8.3)].

Update immunizations according to current immunization guidelines [see Warnings and Precautions (5.10)].

2.2 Important Administration Instructions

● RINVOQ tablets should be taken orally with or without food [see Clinical Pharmacology (12.3)].

● RINVOQ tablets should be swallowed whole. RINVOQ should not be split, crushed, or chewed.

2.3 Recommended Dosage in Rheumatoid Arthritis

The recommended dosage of RINVOQ is 15 mg once daily.

2.4 Recommended Dosage in Psoriatic Arthritis

The recommended dosage of RINVOQ is 15 mg once daily.

2.5 Recommended Dosage in Atopic Dermatitis

Pediatric Patients 12 Years of Age and Older Weighing at Least 40 kg and Adults Less Than 65 Years of Age

Initiate treatment with 15 mg once daily. If an adequate response is not achieved, consider increasing the dosage to 30 mg once daily. Discontinue RINVOQ if an adequate response is not achieved with the 30 mg dose. Use the lowest effective dose needed to maintain response.

Adults 65 Years of Age and Older

The recommended dosage is 15 mg once daily.

2.6 Recommended Dosage in Ulcerative Colitis

Adult Patients: Induction

The recommended induction dosage of RINVOQ is 45 mg once daily for 8 weeks.

Adult Patients: Maintenance

The recommended dosage of RINVOQ for maintenance treatment is 15 mg once daily. A dosage of 30 mg once daily may be considered for patients with refractory, severe or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response.

2.7 Recommended Dosage in Crohn’s Disease

Adult Patients: Induction

The recommended induction dosage of RINVOQ is 45 mg once daily for 12 weeks.

Adult Patients: Maintenance

The recommended dosage of RINVOQ for maintenance treatment is 15 mg once daily. A dosage of 30 mg once daily may be considered for patients with refractory, severe or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response.

2.8 Recommended Dosage in Ankylosing Spondylitis

The recommended dosage of RINVOQ is 15 mg once daily.

2.9 Recommended Dosage in Non-radiographic Axial Spondyloarthritis

The recommended dosage of RINVOQ is 15 mg once daily.

2.10 Recommended Dosage in Patients with Renal Impairment or Hepatic Impairment

Renal Impairment

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis:

● No dosage adjustment is needed for patients with mild, moderate, or severe renal impairment.

Atopic Dermatitis:

● For patients with severe renal impairment [estimated glomerular filtration rate (eGFR) 15 to < 30 mL/min/1.73m2] the recommended dosage is 15 mg once daily [see Use in Specific Populations (8.6)].

● No dosage adjustment is needed for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2).

● RINVOQ is not recommended for use in patients with end stage renal disease (eGFR < 15 mL/min/1.73m2) [see Use in Specific Populations (8.6)].

Ulcerative Colitis:

● For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m2), the recommended dosage is:
• Induction: 30 mg once daily for 8 weeks
• Maintenance: 15 mg once daily

● No dosage adjustment is needed for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2).

● RINVOQ is not recommended for use in patients with end stage renal disease (eGFR < 15 mL/min/1.73m2) [see Use in Specific Populations (8.6)].

Crohn’s Disease:

● For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m2), the recommended dosage is:

• Induction: 30 mg once daily for 12 weeks

• Maintenance: 15 mg once daily

● No dosage adjustment is needed for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2).

● RINVOQ is not recommended for use in patients with end stage renal disease (eGFR < 15 mL/min/1.73m2) [see Use in Specific Populations (8.6)].

Hepatic Impairment

RINVOQ is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7)].

Rheumatoid Arthritis, Psoriatic Arthritis, Atopic Dermatitis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis:

No dosage adjustment is needed for patients with mild or moderate hepatic impairment (Child-Pugh A or B).

Ulcerative Colitis:

For patients with mild to moderate hepatic impairment (Child-Pugh A or B) the recommended dosage is:

• Induction: 30 mg once daily for 8 weeks
  
• Maintenance: 15 mg once daily

Crohn’s Disease:

For patients with mild to moderate hepatic impairment (Child-Pugh A or B) the recommended dosage is:

• Induction: 30 mg once daily for 12 weeks

• Maintenance: 15 mg once daily

2.11 Dosage Modifications Due to Drug Interactions

Rheumatoid Arthritis, Psoriatic Arthritis, Atopic Dermatitis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis

The recommended dosage in patients receiving strong CYP3A4 inhibitors is 15 mg once daily [see Drug Interactions (7.1)].

Ulcerative Colitis

The recommended dosage in patients with ulcerative colitis receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]:

• Induction: 30 mg once daily for 8 weeks
  
• Maintenance: 15 mg once daily

Crohn’s Disease

The recommended dosage in patients with Crohn’s disease receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]:

• Induction: 30 mg once daily for 12 weeks

• Maintenance: 15 mg once daily

2.12 Dosage Interruption

Infections

If a patient develops a serious infection, including serious opportunistic infection, interrupt RINVOQ treatment until the infection is controlled [see Warnings and Precautions (5.1)].

Laboratory Abnormalities

Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 1 [see Warnings and Precautions (5.8)].

5.1 Serious Infections

Serious and sometimes fatal infections have been reported in patients receiving RINVOQ. The most frequent serious infections reported with RINVOQ included pneumonia and cellulitis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis, were reported with RINVOQ.

Avoid use of RINVOQ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating RINVOQ in patients:

• with chronic or recurrent infection
  
• who have been exposed to tuberculosis
  
• with a history of a serious or an opportunistic infection
  
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
  
• with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ. Interrupt RINVOQ if a patient develops a serious or opportunistic infection.

A patient who develops a new infection during treatment with RINVOQ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and RINVOQ should be interrupted if the patient is not responding to antimicrobial therapy. RINVOQ may be resumed once the infection is controlled.

Tuberculosis

Evaluate and test patients for latent and active tuberculosis (TB) infection prior to administration of RINVOQ. Patients with latent TB should be treated with standard antimycobacterial therapy before initiating RINVOQ. RINVOQ should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of RINVOQ in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

During RINVOQ use, monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, were reported in clinical trials with RINVOQ [see Adverse Reactions (6.1)]. The risk of herpes zoster appears to be higher in patients treated with RINVOQ in Japan. If a patient develops herpes zoster, consider temporarily interrupting RINVOQ until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed in accordance with clinical guidelines before starting and during therapy with RINVOQ. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA, were excluded from clinical trials. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical trials. However, cases of hepatitis B reactivation were still reported in patients enrolled in the Phase 3 trials of RINVOQ. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted.

5.2 Mortality

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ.

5.3 Malignancy and Lymphoproliferative Disorders

Malignancies, including lymphomas, were observed in clinical trials of RINVOQ [see Adverse Reactions (6.1)].

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

Non-Melanoma Skin Cancer

NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen.

5.4 Major Adverse Cardiovascular Events

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

5.5 Thrombosis

Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.

If symptoms of thrombosis occur, patients should discontinue RINVOQ and be evaluated promptly and treated appropriately. Avoid RINVOQ in patients that may be at increased risk of thrombosis.

5.6 Hypersensitivity Reactions

Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy [see Adverse Reactions (6.1)].

5.7 Gastrointestinal Perforations

Gastrointestinal perforations have been reported in clinical trials with RINVOQ [see Adverse Reactions (6.1)].

Monitor RINVOQ-treated patients who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis and those taking concomitant medications including NSAIDs or corticosteroids). Evaluate promptly patients presenting with new onset abdominal pain for early identification of gastrointestinal perforation.

5.8 Laboratory Abnormalities

Neutropenia

Treatment with RINVOQ was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3).

Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation and interrupt RINVOQ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3) [see Dosage and Administration (2.1, 2.12)].

Lymphopenia

ALC less than 500 cells/mm3 were reported in RINVOQ-treated patients in clinical trials.

Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation or interrupt RINVOQ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3) [see Dosage and Administration (2.1, 2.12)].

Anemia

Decreases in hemoglobin levels to less than 8 g/dL were reported in RINVOQ-treated patients in clinical trials.

Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation or interrupt RINVOQ treatment in patients with a low hemoglobin level (i.e., less than 8 g/dL) [see Dosage and Administration (2.1, 2.12)].

Lipids

Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol [see Adverse Reactions (6.1)]. Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assess lipid parameters approximately 12 weeks after initiation of treatment, and thereafter according to the clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for the management of hyperlipidemia.

Liver Enzyme Elevations

Treatment with RINVOQ was associated with increased incidence of liver enzyme elevations compared to treatment with placebo.

Evaluate liver enzymes at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury.

If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

5.9 Embryo-Fetal Toxicity

Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in fetal malformations. Verify the pregnancy status of patients of reproductive potential prior to starting treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with RINVOQ and for 4 weeks following completion of therapy [see Use in Specific Populations (8.1, 8.3)].

5.10 Vaccinations

Avoid use of live vaccines during or immediately prior to RINVOQ therapy initiation. Prior to initiating RINVOQ, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.

5.11 Medication Residue in Stool

Reports of medication residue in stool or ostomy output have occurred in patients taking RINVOQ. Most reports described anatomic (e.g., ileostomy, colostomy, intestinal resection) or functional gastrointestinal conditions with shortened gastrointestinal transit times. Instruct patients to contact their healthcare provider if medication residue is observed repeatedly. Monitor patients clinically and consider alternative treatment if there is an inadequate therapeutic response.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Patients with Rheumatoid Arthritis

A total of 3833 patients with rheumatoid arthritis were treated with upadacitinib in the Phase 3 clinical trials of whom 2806 were exposed for at least one year.

Patients could advance or switch to RINVOQ 15 mg from placebo, or be rescued to RINVOQ from active comparator or placebo from as early as Week 12 depending on the trial design.

A total of 2630 patients received at least 1 dose of RINVOQ 15 mg, of whom 1860 were exposed for at least one year. In trials RA-I, RA-II, RA-III and RA-V, 1213 patients received at least 1 dose of RINVOQ 15 mg, of which 986 patients were exposed for at least one year, and 1203 patients received at least 1 dose of upadacitinib 30 mg, of which 946 were exposed for at least one year.

Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg group and at a higher rate than in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (includes oral herpes), and oral candidiasis.

Four integrated datasets are presented in the Specific Adverse Reaction section:

Placebo-controlled Trials: Trials RA-III, RA-IV, and RA-V were integrated to represent safety through 12/14 weeks for placebo (n=1042) and RINVOQ 15 mg (n=1035). Trials RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), RINVOQ 15 mg (n=385), and upadacitinib 30 mg (n=384). Trial RA-IV did not include the 30 mg dose and, therefore, safety data for upadacitinib 30 mg can only be compared with placebo and RINVOQ 15 mg rates from pooling trials RA-III and RA-V.

MTX-controlled Trials: Trials RA-I and RA-II were integrated to represent safety through 12/14 weeks for MTX (n=530), RINVOQ 15 mg (n=534), and upadacitinib 30 mg (n=529).

12-Month Exposure Dataset: Trials RA-I, II, III, and V were integrated to represent the long-term safety of RINVOQ 15 mg (n=1213) and upadacitinib 30 mg (n=1203).

Exposure adjusted incidence rates were adjusted by trial for all the adverse events reported in this section.

Specific Adverse Reactions

Infections

Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, infections were reported in 218 patients (95.7 per 100 patient-years) treated with placebo and 284 patients (127.8 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, infections were reported in 99 patients (136.5 per 100 patient-years) treated with placebo, 118 patients (164.5 per 100 patient-years) treated with RINVOQ 15 mg, and 126 patients (180.3 per 100 patient-years) treated with upadacitinib 30 mg.

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

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

Serious Infections

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

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

12-Month Exposure Dataset: Serious infections were reported in 38 patients (3.5 per 100 patient-years) treated with RINVOQ 15 mg and 59 patients (5.6 per 100 patient-years) treated with upadacitinib 30 mg.

The most frequently reported serious infections were pneumonia and cellulitis.

Tuberculosis

Placebo-controlled Trials and MTX-controlled Trials: In the placebo-controlled period, there were no active cases of tuberculosis reported in the placebo, RINVOQ 15 mg, and upadacitinib 30 mg groups. In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, RINVOQ 15 mg monotherapy, and upadacitinib 30 mg monotherapy groups.

12-Month Exposure Dataset: Active tuberculosis was reported for 2 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg. Cases of extra-pulmonary tuberculosis were reported.

Opportunistic Infections (excluding tuberculosis)

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

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

12-Month Exposure Dataset: Opportunistic infections were reported in 7 patients (0.6 per 100 patient-years) treated with RINVOQ 15 mg and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg.

Malignancies

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

MTX-controlled Trials: Malignancies excluding NMSC were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 0 patients treated with upadacitinib 30 mg monotherapy.

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

Gastrointestinal Perforations

Placebo-controlled Trials: There were no gastrointestinal perforations (based on medical review) reported in patients treated with placebo, RINVOQ 15 mg, and upadacitinib 30 mg.

MTX-controlled Trials: There were no cases of gastrointestinal perforations reported in the MTX and RINVOQ 15 mg group through 12/14 weeks. Two cases of gastrointestinal perforations were observed in the upadacitinib 30 mg group.

12-Month Exposure Dataset: Gastrointestinal perforations were reported in 1 patient treated with RINVOQ 15 mg and 4 patients treated with upadacitinib 30 mg.

Thrombosis

Placebo-controlled Trials: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in 1 patient treated with placebo and 1 patient treated with RINVOQ 15 mg. In RA-V, venous thrombosis was observed in 1 patient treated with RINVOQ 15 mg. There were no observed cases of venous thrombosis reported in RA-III. No cases of arterial thrombosis were observed through 12/14 weeks.

MTX-controlled Trials: In RA-II, venous thrombosis was observed in 0 patients treated with MTX monotherapy, 1 patient treated with RINVOQ 15 mg monotherapy and 0 patients treated with upadacitinib 30 mg monotherapy through Week 14. In RA-II, no cases of arterial thrombosis were observed through 12/14 weeks. In RA-I, venous thrombosis was observed in 1 patient treated with MTX, 0 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg through Week 24. In RA-I, arterial thrombosis was observed in 1 patient treated with upadacitinib 30 mg through Week 24.

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

Laboratory Abnormalities

Hepatic Transaminase Elevations

In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ 15 mg, and in 1.5% and 0.7% of patients treated with placebo, respectively. In RA-III and RA-V, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 1.0% of patients treated with RINVOQ 15 mg, 1.0% and 0% of patients treated with upadacitinib 30 mg and in 1.3% and 1.0% of patients treated with placebo, respectively.

In MTX-controlled trials, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with RINVOQ 15 mg, 1.7% and 1.3% of patients treated with upadacitinib 30 mg and in 1.9% and 0.9% of patients treated with MTX, respectively.

Lipid Elevations

Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Elevations in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In controlled trials, for up to 12/14 weeks, changes from baseline in lipid parameters in patients treated with RINVOQ 15 mg and upadacitinib 30 mg, respectively, are summarized below:

• Mean LDL cholesterol increased by 14.81 mg/dL and 17.17 mg/dL.
  
• Mean HDL cholesterol increased by 8.16 mg/dL and 9.01 mg/dL.
  
• The mean LDL/HDL ratio remained stable.
  
• Mean triglycerides increased by 13.55 mg/dL and 14.44 mg/dL.

Creatine Phosphokinase Elevations

In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the RINVOQ 15 mg and placebo groups, respectively. Most elevations >5 x ULN were transient and did not require treatment discontinuation. In RA-III and RA-V, CPK elevations > 5 x ULN were observed in 0.3% of patients treated with placebo, 1.6% of patients treated with RINVOQ 15 mg, and none in patients treated with upadacitinib 30 mg.

Neutropenia

In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in neutrophil counts, below 1000 cells/mm3 in at least one measurement occurred in 1.1% and <0.1% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in neutrophil counts below 1000 cells/mm3 in at least one measurement occurred in 0.3% of patients treated with placebo, 1.3% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical trials, treatment was interrupted in response to ANC less than 1000 cells/mm3.

Lymphopenia

In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.9% and 0.7% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.5% of patients treated with placebo, 0.5% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg.

Anemia

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

Adverse Reactions in Patients with Psoriatic Arthritis

A total of 1827 patients with psoriatic arthritis were treated with upadacitinib in clinical trials representing 1639.2 patient-years of exposure, of whom 722 were exposed to upadacitinib for at least one year. In the two Phase 3 trials, 907 patients received at least 1 dose of RINVOQ 15 mg, of whom 359 were exposed for at least one year.

Two placebo-controlled trials were integrated (640 patients on RINVOQ 15 mg once daily and 635 patients on placebo) to evaluate the safety of RINVOQ 15 mg in comparison to placebo for up to 24 weeks after treatment initiation.

Overall, the safety profile observed in patients with active psoriatic arthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequencies of herpes zoster and herpes simplex were ≥1% (1.1% and 1.4%, respectively) with RINVOQ 15 mg and 0.8% and 1.3%, respectively with placebo. A higher incidence of acne and bronchitis was also observed in patients treated with RINVOQ 15 mg (1.3% and 3.9%, respectively) compared to placebo (0.3% and 2.7%, respectively).

Adverse Reactions in Patients with Atopic Dermatitis

Three Phase 3 (AD-1, AD-2, and AD-3) and one Phase 2b (AD-4) randomized, double-blind, placebo-controlled, multicenter trials evaluated the safety of RINVOQ in patients with moderate-to-severe atopic dermatitis. The majority of patients were White (68%) and male (57%). The mean age was 34 years (ranged from 12 to 75 years) and 13% of the patients were 12 to less than 18 years. In these 4 trials, 2612 patients were treated with RINVOQ 15 mg or 30 mg orally once daily, with or without concomitant topical corticosteroids (TCS).

In the Phase 3 clinical trials (AD-1, AD-2, and AD-3), a total of 1239 patients received RINVOQ 15 mg, of whom 791 were exposed for at least one year and 1246 patients received RINVOQ 30 mg, of whom 826 were exposed for at least one year.

Trials AD-1, AD-2, and AD-4 compared the safety of RINVOQ monotherapy to placebo through Week 16. Trial AD-3 compared the safety of RINVOQ + TCS to placebo + TCS through Week 16.

Weeks 0 to 16 (Trials AD-1 to AD-4)

In RINVOQ trials with and without TCS (Trials AD-1, 2, 3 and 4) through Week 16, the proportion of patients who discontinued treatment because of adverse reactions in the RINVOQ 15 mg, 30 mg and placebo groups were 2.3%, 2.9% and 3.8%, respectively. Table 3 summarizes the adverse reactions that occurred at a rate of at least 1% in the RINVOQ 15 mg or 30 mg groups during the first 16 weeks of treatment.

Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg and/or 30 mg group and at a higher rate than in the placebo group through Week 16 included anemia, oral candidiasis, pneumonia, non-melanoma skin cancer, and the adverse event of retinal detachment.

The safety profile of RINVOQ through Week 52 was generally consistent with the safety profile observed at Week 16.

Overall, the safety profile observed in patients with AD treated with RINVOQ was similar to the safety profile in patients with RA. Other specific adverse reactions that were reported in patients with AD included eczema herpeticum/Kaposi’s varicelliform eruption.

Eczema Herpeticum/Kaposi’s Varicelliform Eruption

Placebo-controlled Period (16 weeks): Eczema herpeticum was reported in 4 patients (1.6 per 100 patient-years) treated with placebo, 6 patients (2.2 per 100 patient-years) treated with RINVOQ 15 mg and 7 patients (2.6 per 100 patient-years) treated with RINVOQ 30 mg.

12-Month Exposure (Weeks 0 to 52): Eczema herpeticum was reported in 18 patients (1.6 per 100 patient-years) treated with RINVOQ 15 mg and 17 patients (1.5 per 100 patient-years) treated with RINVOQ 30 mg.

Adverse Reactions in Patients with Ulcerative Colitis

RINVOQ was studied up to 8 weeks in patients with moderately to severely active ulcerative colitis in two randomized, double-blind, placebo-controlled induction studies (UC-1, UC-2) and a randomized, double-blind, placebo controlled, dose-finding study (UC-4; NCT02819635). Long term safety up to 52-weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (UC-3) and a long-term extension study [see Clinical Studies (14.4)].

In the two induction studies (UC-1, UC-2) and a dose finding study (UC-4), 1097 patients were enrolled of whom 719 patients received RINVOQ 45 mg once daily.

In the maintenance study (UC-3), 746 patients were enrolled of whom 250 patients received RINVOQ 15 mg once daily and 251 patients received RINVOQ 30 mg once daily.

Adverse reactions reported in ≥2% of patients in any treatment arm in the induction and maintenance studies are shown in Tables 4 and 5, respectively.

Other adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 8 included herpes zoster and pneumonia.

The adverse reaction of non-melanoma skin cancer was reported in 1% of patients in the RINVOQ 30 mg group and none of the patients in the RINVOQ 15 mg or placebo group through Week 52.

The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods.

Overall, the safety profile observed in patients with ulcerative colitis treated with RINVOQ was generally similar to the safety profile in patients with RA and AD.

Specific Adverse Reactions

Serious Infections

Induction Studies: In UC-1, UC-2, and UC-4, serious infections were reported in 5 patients (8.4 per 100 patient-years) treated with placebo and 9 patients (8.4 per 100 patient-years) treated with RINVOQ 45 mg through 8 weeks.

Placebo-controlled Maintenance Study: In UC-3, serious infections were reported in 8 patients (6.3 per 100 patient-years) treated with placebo, 8 patients (4.5 per 100 patient-years) treated with RINVOQ 15 mg, and 6 patients (3.1 per 100 patient-years) treated with RINVOQ 30 mg through 52 weeks.

Laboratory Abnormalities

Hepatic Transaminase Elevations

In studies UC-1, UC-2, and UC-4, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 1.5% of patients treated with RINVOQ 45 mg, and 0% of patients treated with placebo for 8 weeks. AST elevations to ≥ 3 x ULN occurred in 1.5% of patients treated with RINVOQ 45 mg, and 0.3% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN occurred in 0.4% of patients treated with RINVOQ 45 mg and 0% of patients treated with placebo.

In UC-3, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 4% of patients treated with RINVOQ 30 mg, 2% of patients treated with RINVOQ 15 mg, and 0.8% of patients treated with placebo for 52 weeks. Elevations of AST to ≥ 3 x ULN in at least one measurement were observed in 2% of patients treated with RINVOQ 30 mg, 1.6% of patients treated with RINVOQ 15 mg and 0.4% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN were observed in 0.8% of patients treated with 30 mg, 0.4% of patients treated with 15 mg, and 0.4% of patients treated with placebo.

Overall, laboratory abnormalities observed in patients with ulcerative colitis treated with RINVOQ were similar to those described in patients with RA.

Adverse Reactions in Patients with Crohn’s Disease

RINVOQ was studied up to 12 weeks in patients with moderately to severely active CD in two randomized, double-blind, placebo-controlled induction studies (CD-1, CD-2). Long term safety up to 52 weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (CD-3), with additional data provided from a long-term extension (LTE) period [see Clinical Studies (14.5)].

In the two induction studies (CD-1, CD-2), 1021 patients were enrolled, of whom 674 patients received RINVOQ 45 mg once daily during the placebo-controlled period.

In the maintenance study (CD-3), 673 patients were enrolled, of whom 221 patients received RINVOQ 15 mg once daily and 229 patients received RINVOQ 30 mg once daily during the randomized, placebo-controlled period.

Overall, the safety profile observed in patients with Crohn’s disease treated with RINVOQ was consistent with the known safety profile for RINVOQ in other indications.

Adverse reactions reported in ≥2% of patients treated with RINVOQ and at a higher rate than placebo in the induction and maintenance studies are shown in Tables 6 and 7, respectively.

Adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 12 included folliculitis, hypercholesterolemia, bronchitis, pneumonia, oral candidiasis, and hyperlipidemia.

Adverse reactions reported in less than 2% of patients in the RINVOQ 15 mg or 30 mg group and at a higher rate than in the placebo group through Week 52 included hyperlipidemia, oral candidiasis, and hypercholesterolemia.

The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods.

Specific Adverse Reactions

Serious Infections

Induction Studies: In CD-1 and CD-2, serious infections were reported in 6 patients (8 per 100 patient-years) treated with placebo and 13 patients (9 per 100 patient-years) treated with RINVOQ 45 mg through 12 weeks of the placebo-controlled period.

Maintenance Study/LTE: In the long-term placebo-controlled period, serious infections were reported in 10 patients (7 per 100 patient-years) treated with placebo, 7 patients (4 per 100 patient-years) treated with RINVOQ 15 mg, and 13 patients (6 per 100 patient-years) treated with RINVOQ 30 mg.

Gastrointestinal Perforations

Induction Studies: During the induction studies in all patients treated with RINVOQ 45 mg (N=938), gastrointestinal perforation was reported in 4 patients (2 per 100 patient-years). In the placebo-controlled induction period, in CD-1 and CD-2, gastrointestinal perforation was reported in no patients treated with placebo (N=347) and 1 patient (1 per 100 patient-years) treated with RINVOQ 45 mg (N=674) through 12 weeks.

Maintenance Study/LTE: In the long-term placebo-controlled period, gastrointestinal perforation was reported in 1 patient (1 per 100 patient-years) treated with placebo, 1 patient (<1 per 100 patient-years) treated with RINVOQ 15 mg, and 1 patient (<1 per 100 patient-years) treated with RINVOQ 30 mg.

Patients who received placebo or RINVOQ 15 mg for maintenance therapy and lost response were treated with rescue RINVOQ 30 mg (N=336). Among these patients, gastrointestinal perforation was reported in 3 patients (1 per 100 patient-years) through long-term treatment.

Adverse Reactions in Patients with Ankylosing Spondylitis

A total of 596 patients with ankylosing spondylitis were treated with RINVOQ 15 mg in the two clinical trials representing 577.3 patient-years of exposure, of whom 220 were exposed to RINVOQ 15 mg for at least one year.

Overall, the safety profile observed in patients with active ankylosing spondylitis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis and psoriatic arthritis. During the 14-week placebo-controlled period in Trial AS-I, the frequency of headache was 5.4% with RINVOQ 15 mg and 2.1% with placebo. During the 14-week placebo-controlled period in Trial AS-II, the frequency of headache was 3.3% with RINVOQ 15 mg and 1.4% with placebo.

Adverse Reactions in Patients with Non-radiographic Axial Spondyloarthritis

A total of 187 patients with non-radiographic axial spondyloarthritis were treated with RINVOQ 15 mg in the clinical trial representing 116.6 patient-years of exposure, of whom 31 were exposed to RINVOQ 15 mg for at least one year.

Overall, the safety profile observed in patients with active non-radiographic axial spondyloarthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

7.1 Strong CYP3A4 Inhibitors

Upadacitinib exposure is increased when RINVOQ is co-administered with a strong CYP3A4 inhibitor (such as ketoconazole, clarithromycin, and grapefruit), which may increase the risk of RINVOQ adverse reactions [see Clinical Pharmacology (12.3)]. Monitor patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondylarthritis closely for adverse reactions when co-administering RINVOQ 15 mg once daily with strong CYP3A4 inhibitors. Food or drink containing grapefruit should be avoided during treatment with RINVOQ.

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

For patients with ulcerative colitis or Crohn’s disease taking strong CYP3A4 inhibitors, reduce the RINVOQ induction dosage to 30 mg once daily. The recommended maintenance dosage is 15 mg once daily [see Dosage and Administration (2.11)].

7.2 Strong CYP3A4 Inducers

Upadacitinib exposure is decreased when RINVOQ is co-administered with strong CYP3A4 inducers (such as rifampin), which may lead to reduced therapeutic effect of RINVOQ [see Clinical Pharmacology (12.3)]. Coadministration of RINVOQ with strong CYP3A4 inducers is not recommended.

8.1 Pregnancy

Risk Summary

Available data from the pharmacovigilance safety database and postmarketing case reports on use of RINVOQ in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. Based on animal studies, RINVOQ has the potential to adversely affect a developing fetus. Advise patients of reproductive potential and pregnant patients of the potential risk to the fetus.

In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the 15 mg dose, 0.8 and 7.6 times the 30 mg dose, and 0.6 and 5.6 times the maximum recommended human dose (MRHD) of 45 mg (on an AUC basis) resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib during organogenesis at exposures approximately 0.29 and 2.2 times the 15 mg dose, 0.15 times and 1.1 times the 30 mg dose, and at 0.11 and 0.82 times the MRHD (on an AUC basis). In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 3 times the 15 mg dose, 1.4 times the 30 mg dose, and the same as the MRHD (on an AUC basis) resulted in no maternal or developmental toxicity (see Data).

The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages are 2-4% and 15-20%, respectively.

Report pregnancies to the AbbVie Inc.’s Adverse Event reporting line at 1-800-633-9110, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or inflammatory bowel disease. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data

Animal Data

In an oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 5, 25, and 75 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that consisted of misshapen humerus and bent scapula) at exposures equal to or greater than approximately 1.7 times the 15 mg dose, 0.9 times the 30 mg dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 5 mg/kg/day and higher). Additional skeletal malformations (bent forelimbs/hindlimbs and rib/vertebral defects) and decreased fetal body weights were observed in the absence of maternal toxicity at an exposure approximately 84 times the 15 mg dose, 43 times the 30 mg dose, and 31 times the MRHD (on an AUC basis at a maternal oral dose of 75 mg/kg/day).

In a second oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 1.5 and 4 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that included bent humerus and scapula) at exposures approximately 1.6 times the 15 mg dose, 0.8 times the 30 mg dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 4 mg/kg/day). No developmental toxicity was observed in rats at an exposure approximately 0.29 times the 15 mg dose, 0.15 times the 30 mg dose, and 0.11 times the MRHD (on an AUC basis at a maternal oral dose of 1.5 mg/kg/day).

In an oral embryo-fetal developmental study, pregnant rabbits received upadacitinib at doses of 2.5, 10, and 25 mg/kg/day during the period of organogenesis from gestation day 7 to 19. Embryolethality, decreased fetal body weights, and cardiovascular malformations were observed in the presence of maternal toxicity at an exposure approximately 15 times the 15 mg dose, 7.6 times the 30 mg dose, and 5.6 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both total and early resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 2.2 times the 15 mg dose, 1.1 times the 30 mg dose, and 0.82 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

In an oral pre- and post-natal development study, pregnant female rats received upadacitinib at doses of 2.5, 5, and 10 mg/kg/day from gestation day 6 through lactation day 20. No maternal or developmental toxicity was observed in either mothers or offspring, respectively, at an exposure approximately 3 times the 15 mg dose, 1.4 times the 30 mg dose, and at approximately the same exposure as the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

8.2 Lactation

Risk Summary

There are no data on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with RINVOQ, and for 6 days (approximately 10 half-lives) after the last dose.

Data

A single oral dose of 10 mg/kg radiolabeled upadacitinib was administered to lactating female Sprague-Dawley rats on post-partum days 7-8. Drug exposure was approximately 30-fold greater in milk than in maternal plasma based on AUC0-t values. Approximately 97% of drug-related material in milk was parent drug.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ [see Use in Specific Populations (8.1)].

Contraception

Females

Based on animal studies, upadacitinib may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose.

8.4 Pediatric Use

Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis

The safety and effectiveness of RINVOQ in pediatric patients with juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, or non-radiographic axial spondyloarthritis have not been established.

Atopic Dermatitis

The safety and effectiveness of RINVOQ in pediatric patients 12 years of age and older weighing at least 40 kg with atopic dermatitis have been established. A total of 344 pediatric patients aged 12 to 17 years with moderate to severe atopic dermatitis were randomized across three trials (AD-1, AD-2 and AD-3) to receive either RINVOQ 15 mg (N=114) or 30 mg (N=114) or matching placebo (N=116) in monotherapy or combination with topical corticosteroids. Efficacy was consistent between the pediatric patients and adults [see Clinical Studies (14.3)]. The adverse reaction profile in the pediatric patients was similar to the adults [see Adverse Reactions (6.1)].

The safety and effectiveness of RINVOQ in pediatric patients less than 12 years of age with atopic dermatitis have not been established.

Ulcerative Colitis and Crohn’s Disease

The safety and effectiveness of RINVOQ in pediatric patients with ulcerative colitis and Crohn’s disease have not been established.

8.5 Geriatric Use

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 75 years and 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 75 years and older. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of overall adverse events, including serious infections, in patients 65 years of age and older.

Atopic Dermatitis

Of the 2583 patients treated in the three Phase 3 clinical trials, a total of 120 patients with atopic dermatitis were 65 years of age or older, including 6 patients 75 years of age. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of serious infections and malignancies in those patients 65 years of age or older in the 30 mg dosing group in the long-term trials.

Ulcerative Colitis

Of the 1097 patients treated in the controlled clinical trials, a total of 95 patients with ulcerative colitis were 65 years and older. Clinical studies of RINVOQ did not include sufficient numbers of patients 65 years of age and older with ulcerative colitis to determine whether they respond differently from younger adult patients.

Crohn’s Disease

Of the 1021 patients who were treated in the controlled induction clinical trials, a total of 39 patients with Crohn’s disease were 65 years of age or older, and no patients were 75 years of age or older. Clinical studies of RINVOQ did not include sufficient numbers of patients 65 years of age and older with Crohn’s disease to determine whether they respond differently from younger adult patients.

Ankylosing Spondylitis

Of the 607 patients treated in the controlled clinical trials, a total of 32 patients with ankylosing spondylitis were 65 years and older. Clinical studies of RINVOQ did not include sufficient numbers of patients 65 years of age and older with ankylosing spondylitis to determine whether they respond differently from younger adult patients.

Non-radiographic Axial Spondyloarthritis

Of the 313 patients treated in a phase 3 clinical trial, a total of 9 patients with non-radiographic axial spondyloarthritis were 65 years and older. Clinical studies of RINVOQ did not include sufficient numbers of patients 65 years of age and older with non-radiographic axial spondyloarthritis to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment

For patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or non-radiographic axial spondyloarthritis, no dosage adjustment is needed in patients with mild (eGFR 60 to < 90 mL/min/1.73 m2), moderate (eGFR 30 to < 60 mL/min/1.73 m2), or severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2).

For patients with atopic dermatitis, the maximum recommended dosage is 15 mg once daily for patients with severe renal impairment. No dosage adjustment is needed in patients with mild or moderate renal impairment.

For patients with ulcerative colitis or Crohn’s disease, the recommended dosage for severe renal impairment is 30 mg once daily for induction and 15 mg once daily for maintenance. No dosage adjustment is needed in patients with mild or moderate renal impairment [see Dosage and Administration (2.10)].

RINVOQ has not been studied in patients with end stage renal disease (eGFR <15 mL/min/1.73m2). Use in patients with atopic dermatitis, ulcerative colitis, or Crohn’s disease with end stage renal disease is not recommended [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The use of RINVOQ has not been studied in patients with severe hepatic impairment (Child Pugh C), and therefore not recommended for use in patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondyloarthritis [see Dosage and Administration (2.10) and Clinical Pharmacology (12.3)].

For patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis no dosage adjustment is needed in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment.

For patients with ulcerative colitis or Crohn’s disease, the recommended dosage for mild to moderate hepatic impairment is 30 mg once daily for induction and 15 mg once daily for maintenance [see Dosage and Administration (2.10)].

12.1 Mechanism of Action

Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Upadacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In a cell-free isolated enzyme assay, upadacitinib had greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2. In human leukocyte cellular assays, upadacitinib inhibited cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 more potently than JAK2/JAK2 mediated STAT phosphorylation. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.

12.2 Pharmacodynamics

Inhibition of IL-6 Induced STAT3 and IL-7 Induced STAT5 Phosphorylation

In healthy volunteers, the administration of upadacitinib (immediate release formulation) resulted in a dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2)-induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. The maximal inhibition was observed 1 hour after dosing which returned to near baseline by the end of dosing interval.

Lymphocytes

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline up to Week 36 which gradually returned to, at or near baseline levels with continued treatment.

Immunoglobulins

In patients with rheumatoid arthritis, small decreases from baseline in mean IgG and IgM levels were observed with upadacitinib treatment in the controlled period; however, the mean values at baseline and at all visits were within the normal reference range.

Cardiac Electrophysiology

At 2.5 times the mean exposure of the maximum therapeutic dose, 45 mg once daily dose, there was no clinically relevant effect on the QTc interval.

12.3 Pharmacokinetics

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. After a single dose administration of RINVOQ 15 mg, 30 mg, and 45 mg under fasting condition in healthy subjects, mean Cmax was 31.6 ng/mL, 71.8 ng/mL, and 90.7 ng/mL, respectively, and mean AUCinf was 265 ng·h/mL, 543 ng·h/mL, and 752 ng·h/mL, respectively. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after once daily administration. Upadacitinib pharmacokinetics are comparable between rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondyloarthritis patients.

Absorption

Following oral administration of upadacitinib extended-release formulation, upadacitinib is absorbed with a median Tmax of 2 to 4 hours.

Coadministration of upadacitinib with a high-fat/ high-calorie meal had no clinically relevant effect on upadacitinib exposures (increased AUCinf by 29% and Cmax by 39% to 60%). In clinical trials, upadacitinib was administered without regard to meals [see Dosage and Administration (2.2)].

Distribution

Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components with a blood to plasma ratio of 1.0.

Elimination

Metabolism

Upadacitinib metabolism is mediated by mainly CYP3A4 with a potential minor contribution from CYP2D6. The pharmacologic activity of upadacitinib is attributed to the parent molecule. In a human radiolabeled study, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma while the main metabolite detected (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.

Excretion

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

Specific Populations

Body Weight, Gender, and Race

Body weight, gender, race, and ethnicity did not have a clinically meaningful effect on upadacitinib exposure.

Pediatric Patients

No meaningful difference in the systemic exposure of upadacitinib was observed in pediatric patients with atopic dermatitis 12 years of age and older weighing at least 40 kg compared to adults.

Geriatric Patients

No clinically meaningful differences in the pharmacokinetics of upadacitinib were observed in geriatric patients (≥ 65 years of age) compared to younger adult patients.

Patients with Renal Impairment

Upadacitinib mean AUCinf after a single dose administration of 15 mg upadacitinib was 18%, 33%, and 44% higher in patients with mild (eGFR 60 to < 90 mL/min/1.73 m2), moderate (eGFR 30 to < 60 mL/min/1.73 m2), and severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), respectively, compared to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). Upadacitinib mean Cmax was similar among subjects with normal and impaired renal function. In patients receiving 15 mg, 30 mg, or 45 mg once daily upadacitinib, mild and moderate renal impairment is not expected to have a clinically relevant effect on upadacitinib exposure [see Dosage and Administration (2.10) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Upadacitinib mean AUCinf after a single dose administration of 15 mg upadacitinib was 28% and 24% higher in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib mean Cmax was unchanged in patients with mild hepatic impairment and 43% higher in patients with moderate hepatic impairment compared to subjects with normal liver function. Upadacitinib was not studied in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.10) and Use in Specific Populations (8.7)].

Drug Interaction Studies

Potential for Other Drugs to Influence the Pharmacokinetics of Upadacitinib

Upadacitinib is metabolized in vitro by CYP3A4 with a minor contribution from CYP2D6. The effect of co-administered drugs on upadacitinib plasma exposures is provided in Table 8 [see Drug Interactions (7)].

pH modifying medications (e.g., antacids or proton pump inhibitors) are not expected to affect upadacitinib plasma exposures based on in vitro assessments and population pharmacokinetic analyses. CYP2D6 metabolic phenotype had no effect on upadacitinib pharmacokinetics (based on population pharmacokinetic analyses), indicating that inhibitors of CYP2D6 have no clinically relevant effect on upadacitinib exposures.

Potential for Upadacitinib to Influence the Pharmacokinetics of Other Drugs

In vitro studies indicate that upadacitinib does not inhibit the activity of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at clinically relevant concentrations. In vitro studies indicate that upadacitinib induces CYP3A4 but does not induce CYP2B6 or CYP1A2 at clinically relevant concentrations. In vitro studies indicate that upadacitinib does not inhibit the transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations.

Clinical studies indicate that upadacitinib has no clinically relevant effects on the pharmacokinetics of co-administered drugs. Following upadacitinib 30 mg and 45 mg once daily, the effects on each CYP enzymes (CYP1A2, CYP3A, CYP2C9, and CYP2C19) were similar between two doses except for the effect on CYP2D6. Following upadacitinib 30 mg and 45 mg once daily, a weak induction of CYP3A4 was observed. A weak inhibition of CYP2D6 was observed at upadacitinib 45 mg but not at 30 mg. Summary of results from clinical studies which evaluated the effect of upadacitinib on other drugs is provided in Table 9.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 that received upadacitinib for up to 101 weeks at oral doses up to 15 or 20 mg/kg/day, respectively (approximately 4 and 10 times the 15 mg dose, 2 and 5 times the 30 mg dose, and 1.6 and 4 times the maximum recommended human dose (MRHD) of 45 mg on an AUC basis, respectively). No evidence of tumorigenicity was observed in male or female Tg.rasH2 mice that received upadacitinib for 26 weeks at oral doses up to 20 mg/kg/day.

Mutagenesis

Upadacitinib tested negative in the following genotoxicity assays: the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

Upadacitinib had no effect on fertility in male or female rats at oral doses up to 50 mg/kg/day in males and 75 mg/kg/day in females (approximately 42 and 84 times the 15 mg dose, 22 and 43 times the 30 mg dose, and 16 and 31 times the MRHD, respectively, on an AUC basis). However, maintenance of pregnancy was adversely affected at oral doses of 25 mg/kg/day and 75 mg/kg/day based upon dose-related findings of increased post-implantation losses (increased resorptions) and decreased numbers of mean viable embryos per litter (approximately 22 and 84 times the 15 mg dose, 11 and 43 times the 30 mg dose, and 8 and 31 times the MRHD on an AUC basis, respectively). The number of viable embryos was unaffected in female rats that received upadacitinib at an oral dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 2 times the 15 mg dose, 0.9 times the 30 mg dose, and at 0.6 times the MRHD on an AUC basis).

14.1 Rheumatoid Arthritis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in five Phase 3 randomized, double-blind, multicenter trials in patients with moderately to severely active rheumatoid arthritis and fulfilling the ACR/EULAR 2010 classification criteria. Patients 18 years of age and older were eligible to participate. The presence of at least 6 tender and 6 swollen joints and evidence of systemic inflammation based on elevation of hsCRP was required at baseline. Although other doses have been studied, the recommended dosage of RINVOQ is 15 mg once daily.

Trial RA-I (NCT02706873) was a 24-week monotherapy trial in 947 patients with moderately to severely active rheumatoid arthritis who were naïve to methotrexate (MTX). Patients received RINVOQ 15 mg or upadacitinib 30 mg orally once daily or MTX as monotherapy. At Week 26, non-responding patients on upadacitinib could be rescued with the addition of MTX, while patients on MTX could be rescued with the addition of blinded RINVOQ 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients who achieved 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 Sharp Score (mTSS) at Week 24.

Trial RA-II (NCT02706951) was a 14-week monotherapy trial 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 their stable dose of MTX monotherapy. At Week 14, patients who were randomized to MTX were advanced to RINVOQ 15 mg or upadacitinib 30 mg once daily monotherapy in a blinded manner based on pre-determined assignment 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.

Trial RA-III (NCT02675426) was a 12-week trial in 661 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to conventional disease modifying anti-rheumatic drugs (cDMARDs). Patients received RINVOQ 15 mg or upadacitinib 30 mg once daily or placebo added to background cDMARD therapy. At Week 12, patients who were randomized to placebo were advanced to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner based on pre-determined assignment at baseline. The primary endpoint was the proportion of patients who achieved 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.

Trial RA-IV (NCT02629159) was a 48-week trial in 1629 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to MTX. Patients received RINVOQ 15 mg once daily, active comparator, or placebo added to background MTX. From Week 14, non-responding patients on RINVOQ 15 mg could be rescued to active comparator in a blinded manner, and non-responding patients on active comparator or placebo could be rescued to RINVOQ 15 mg in a blinded manner. 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 who achieved an ACR20 response at Week 12 versus placebo. 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.

Trial RA-V (NCT02706847) was a 12-week trial 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 added to background cDMARD therapy. At Week 12, patients who were randomized to placebo were advanced to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner based on pre-determined assignment at baseline. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. Key secondary endpoints included DAS28-CRP ≤3.2 and change from baseline in HAQ-DI at Week 12.

Clinical Response

The percentages of RINVOQ-treated patients achieving ACR20, ACR50, and ACR70 responses, and DAS28(CRP) < 2.6 in all trials are shown in Table 10.

Patients treated with RINVOQ 15 mg, alone or in combination with cDMARDs, achieved higher ACR response rates compared to MTX monotherapy or placebo, respectively, at the primary efficacy timepoint (Table 10).

In Trial IV, the percent of patients achieving ACR20 response by visit is shown in Figure 1.

In Trials RA-III and RA-V, higher ACR20 response rates were observed at 1 week with RINVOQ 15 mg versus placebo.

Treatment with RINVOQ 15 mg, alone or in combination with cDMARDs, resulted in greater improvements in the ACR components compared to MTX or placebo at the primary efficacy timepoint (Table 11).

Figure 1. Percent of Patients Achieving ACR20 in Trial RA-IV

Abbreviations: ACR20 = American College of Rheumatology ≥20% improvement; MTX = methotrexate
Patients who discontinued randomized treatment, or were missing ACR20 results, or were lost-to-follow-up or withdrawn from the trial were imputed as non-responders.

In RA-I and RA-IV, a higher proportion of patients treated with RINVOQ 15 mg alone or in combination with MTX, achieved DAS28-CRP < 2.6 compared to MTX or placebo at the primary efficacy timepoint (Table 12).

Radiographic Response

Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score, at Week 26 in Trial RA-IV and Week 24 in Trial RA-I. The proportion of patients with no radiographic progression (mTSS change from baseline ≤ 0) was also assessed.

In Trial RA-IV, treatment with RINVOQ 15 mg inhibited the progression of structural joint damage compared to placebo in combination with cDMARDs at Week 26 (Table 13). Analyses of erosion and joint space narrowing scores were consistent with overall results.

In the placebo plus MTX group, 76% of the patients experienced no radiographic progression at Week 26 compared to 83% of the patients treated with RINVOQ 15 mg.

In Trial RA-I, treatment with RINVOQ 15 mg monotherapy inhibited the progression of structural joint damage compared to MTX monotherapy at Week 24 (Table 13). Analyses of erosion and joint space narrowing scores were consistent with overall results.

In the MTX monotherapy group, 78% of the patients experienced no radiographic progression at Week 24 compared to 87% of the patients treated with RINVOQ 15 mg monotherapy.

Physical Function Response

Treatment with RINVOQ 15 mg, alone or in combination with cDMARDs, resulted in a greater improvement in physical function at Week 12/14 compared to all comparators as measured by HAQ-DI.

Other Health-Related Outcomes

In all trials except for Trial RA-V, patients receiving RINVOQ 15 mg had greater improvement from baseline in physical component summary (PCS) score, mental component summary (MCS) scores, and in all 8 domains of the Short Form Health Survey (SF-36) compared to placebo in combination with cDMARDs or MTX monotherapy at Week 12/14.

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

14.2 Psoriatic Arthritis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in two Phase 3 randomized, double-blind, multicenter, placebo-controlled trials in patients 18 years of age or older with moderately to severely active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender joints and at least 3 swollen joints, and active plaque psoriasis or history of plaque psoriasis. Although another dose has been studied, the recommended dose of RINVOQ is 15 mg once daily for psoriatic arthritis.

Trial PsA-I (NCT03104400) was a 24-week trial in 1705 patients with moderately to severely active psoriatic arthritis who had an inadequate response or intolerance 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 to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Trial PsA-II (NCT03104374) was a 24-week trial 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 to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Clinical Response

In both trials, patients treated with RINVOQ 15 mg achieved significantly higher ACR20 responses compared to placebo at Week 12 (Table 14, Figure 2). A higher proportion of patients treated with RINVOQ 15 mg achieved ACR50 and ACR70 responses at Week 12 compared to placebo.

Treatment with RINVOQ 15 mg resulted in improvements in the ACR components compared to placebo at the primary efficacy timepoint (Table 15).

The percentage of patients achieving ACR20 response by visit is shown in Figure 2.

Figure 2. Percent of Patients Achieving ACR20 in Trial PsA-II

Abbreviations: ACR20 = American College of Rheumatology ≥20% improvement Patients who discontinued randomized treatment, or were missing ACR20 results, or were lost-to-follow-up or withdrawn from the trial were imputed as non-responders.

Treatment with RINVOQ 15 mg resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.

Treatment with RINVOQ 15 mg resulted in improvement in skin manifestations in patients with PsA. However, RINVOQ has not been studied in and is not indicated for the treatment of plaque psoriasis.

Physical Function Response

In both trials, patients treated with RINVOQ 15 mg showed significant improvement in physical function from baseline compared to placebo as assessed by HAQ-DI at Week 12 (Table 14). The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 12 was -0.28 (-0.35, -0.22) in Trial PsA-I and -0.21 (-0.30, -0.12) in Trial PsA-II.

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

Radiographic Response

In Trial PsA-I, inhibition of progression of structural damage was assessed radiographically and expressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, the erosion score and the joint space narrowing score, at Week 24.

Treatment with RINVOQ 15 mg inhibited progression of structural joint damage compared to placebo at Week 24 (Table 16). Analyses of erosion and joint space narrowing scores were consistent with overall results. The proportion of patients with no radiographic progression (mTSS change ≤ 0) at Week 24 was 93% in patients receiving RINVOQ 15 mg and 89% in patients receiving placebo.

Other Health-Related Outcomes

Health-related quality of life was assessed by SF-36. In both trials, patients receiving RINVOQ 15 mg experienced significantly greater improvement from baseline in the Physical Component Summary score compared to placebo at Week 12. Greater improvement was also observed in the Mental Component Summary score and all 8 domains of SF-36 compared to placebo.

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 trials.

14.3 Atopic Dermatitis

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

Disease severity at baseline was defined by a validated Investigator's Global Assessment (vIGA-AD) score ≥3 in the overall assessment of AD on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16, a minimum body surface area (BSA) involvement of ≥10%, and weekly average Worst Pruritus Numerical Rating Scale (NRS) score ≥4. Overall, 57% of the patients were male and 69% were white. The mean age at baseline was 34 years (ranged from 12 to 75 years) and 13% of the patients were 12 to less than 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 baseline mean EASI score was 29 and the baseline weekly average Worst Pruritus NRS score was 7. Approximately 52% of the patients had prior exposure to systemic AD treatment.

In all three trials, patients received RINVOQ once daily oral doses of 15 mg, 30 mg, or matching placebo for 16 weeks. In Trial AD-3, patients also received RINVOQ or placebo with concomitant topical corticosteroids (TCS) for 16 weeks.

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

Clinical Response

Monotherapy Trials (AD-1 and AD-2)

The results of RINVOQ monotherapy trials (AD-1 and AD-2) are presented in Table 17. Figure 3 presents the proportion of patients with ≥ 4-point improvement in Worst Pruritus NRS at Weeks 1, 4, and 16 for Trials AD-1 and AD-2.

Figure 3. Proportion of Patients with Moderate to Severe AD with ≥4-point Improvement in the Worst Pruritus NRS in Monotherapy Trials

Examination of age, gender, race, weight, and prior systemic treatment with immunosuppressants did not identify differences in response to RINVOQ among these subgroups in Trials AD-1 and AD-2.

Concomitant TCS Trial (AD-3)

The results of the RINVOQ with concomitant TCS trial (AD-3) are presented in Table 18. Figure 4 presents the proportion of patients with ≥ 4-point improvement in Worst Pruritus NRS at Weeks 1, 4, and 16 for Trial AD-3.

Figure 4. Proportion of Patients with Moderate to Severe AD with ≥4-point Improvement in the Worst Pruritus NRS in Concomitant TCS Trial

Examination of age, gender, race, weight, and prior systemic treatment with immunosuppressants did not identify differences in response to RINVOQ among these subgroups in Trial AD-3.

Pediatric Patient Population

The efficacy results of the RINVOQ monotherapy trials (AD-1 and AD-2) and the RINVOQ with concomitant TCS trial (AD-3) at Week 16 for pediatric patients 12 years of age and older are presented in Table 19 and Table 20, respectively.

14.4 Ulcerative Colitis

Induction Trials (Study UC-1 and Study UC-2)

In two identical induction trials (UC-1; NCT02819635 and UC-2; NCT03653026), patients were randomized 2:1 to receive either RINVOQ 45 mg once daily or placebo for 8 weeks. A total of 988 patients were analyzed across the two trials. These trials included adult patients with moderately to severely active ulcerative colitis who had an inadequate response, loss of response, or intolerance to oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapy. Enrolled patients were permitted to use stable doses of oral aminosalicylates, methotrexate, ulcerative colitis-related antibiotics, and/or oral corticosteroids (up to 30 mg/day prednisone or equivalent). At baseline, 38% of patients were receiving corticosteroids, and 68% of patients were receiving aminosalicylates. Concomitant biologic therapies, azathioprine, 6-mercaptopurine, intravenous or rectal corticosteroids were prohibited. A total of 51% of patients had previously failed treatment with or were intolerant to at least one biologic therapy. RINVOQ is indicated for patients who have an inadequate response or intolerance to one or more TNF blockers [see Indications and Usage (1.4)].

Disease activity was assessed on the modified Mayo score (mMS), a 3-component Mayo score (0-9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SFS), rectal bleeding (RBS), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions, and a score of 3 was defined by spontaneous bleeding and ulceration. Enrolled patients had a mMS between 5 to 9 with an ES of 2 or 3; at baseline the median mMS was 7, with 61% of patients having a baseline mMS of 5 to 7 and 39% having a mMS of 8 to 9.

At baseline, 39% and 37% of patients received corticosteroids, 1% and 1% of patients received methotrexate, and 68% and 69% of patients received aminosalicylates in UC-1 and UC-2, respectively. Patient disease activity was moderate (mMS ≤7) in 61% and 60% of patients and severe (mMS >7) in 39% and 40% of patients in UC-1 and UC-2, respectively.

The primary endpoint was clinical remission defined using the mMS at Week 8. Secondary endpoints included clinical response, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 21 and Table 22).

Studies UC-1 and UC-2 were not designed to evaluate the relationship of histologic endoscopic mucosal improvement at Week 8 to disease progression and long-term outcomes.

Rectal Bleeding and Stool Frequency Subscores

Onset of clinical response was assessed using the SFS and RBS (partial modified Mayo Score [pmMS]). Initial response was defined as a decrease of ≥1 point and ≥30% from baseline in pmMS and a decrease in RBS ≥1 or an absolute RBS≤1. Onset of response occurred as early as Week 2 in a greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo.

Endoscopic and Histologic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. At Week 8, a greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo achieved endoscopic remission (UC-1: 14% vs 1%, UC-2: 18% vs 2%). Endoscopic remission with Geboes histologic score < 2.0 (indicating no neutrophils in crypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue) was achieved by a greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo at Week 8 (UC-1: 11% vs 1%, UC-2: 13% vs 2%).

Abdominal Pain and Bowel Urgency

A greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo had no abdominal pain (UC-1: 47% vs 23%, UC-2: 54% vs 24%) and no bowel urgency (UC-1: 48% vs 21%, UC-2: 54% vs 26%) at Week 8.

Fatigue

In Studies UC-1 and UC-2, patients treated with RINVOQ experienced a clinically meaningful improvement in fatigue, as assessed by change from baseline in FACIT-F score, at Week 8, compared to placebo-treated patients. The effect of RINVOQ to improve fatigue after 8 weeks of induction has not been established.

Maintenance Study UC-3

In UC-3 (NCT02819635), a total of 451 patients who received RINVOQ 45 mg once daily in either UC-1, UC-2 or UC-4 and achieved clinical response were re-randomized to receive RINVOQ 15 mg, 30 mg or placebo once daily for up to 52 weeks.

The primary endpoint was clinical remission defined using mMS at Week 52. Secondary endpoints included corticosteroid-free clinical remission, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 23).

The relationship between histologic endoscopic mucosal improvement at Week 52 and disease progression and longer-term outcomes after Week 52 was not evaluated in Study UC-3.

Endoscopic and Histologic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. In UC-3, a greater proportion of patients treated with RINVOQ 15 mg and 30 mg once daily compared to placebo achieved endoscopic remission at Week 52 (24% and 26% vs 6%). Endoscopic remission with Geboes histologic score < 2.0 was achieved by a greater proportion of patients treated with RINVOQ 15 mg and 30 mg once daily compared to placebo at Week 52 (18% and 19% vs 5%).

Abdominal Pain and Bowel Urgency

At Week 52, a greater proportion of patients treated with RINVOQ 15 mg and 30 mg once daily compared to placebo had no abdominal pain (46%, 55% and 21%, respectively) and no bowel urgency (56%, 64% and 17%, respectively).

14.5 Crohn’s Disease

Induction Trials (Studies CD-1 and CD-2)

In two induction trials, CD-1 (NCT03345836) and CD-2 (NCT03345849), patients were randomized 2:1 to receive RINVOQ 45 mg or placebo once daily for 12 weeks. Efficacy was assessed in a population of 857 patients (419 patients in CD-1 and 438 patients in CD-2) with moderately to severely active Crohn’s disease (CD), with baseline Crohn’s Disease Activity Index (CDAI) score of at least 220 and centrally-reviewed Simple Endoscopic Score for Crohn’s Disease (SES-CD) of ≥ 6, or ≥ 4 for isolated ileal disease, excluding the narrowing component. In CD-1, all patients had inadequate response or were intolerant to treatment with one or more biological therapies (prior biologic failure). In CD-2, 45% (197/438) of patients had inadequate response or were intolerant to treatment with one or more biological therapies (prior biologic failure). Enrolled patients in both studies were permitted to use stable doses of CD-related antibiotics, aminosalicylates, or methotrexate. Concomitant corticosteroids (up to 30 mg/day prednisone or equivalent) were permitted at enrollment; tapering was initiated at Week 4.

In CD-1, patients had a mean age of 37 years (range 18 to 74 years); 46% were female; and 72% identified as White, 21% as Asian, 6% as Black or African American, 0.5% as American Indian or Alaska Native, and 0.5% as multiple racial groups. In CD-2, patients had a mean age of 40 years (range of 18 to 74 years); 45% were female; 74% identified as White, 20% as Asian, 4% as Black or African American, and 2% as multiple racial groups.

At baseline, 36% and 37% of patients received corticosteroids, 7% and 3% of patients received methotrexate, 15% and 24% of patients received aminosalicylates, and 2% and 1% of patients received CD-related antibiotics in CD-1 and CD-2, respectively.

The co-primary endpoints were the proportion of patients achieving clinical remission (by CDAI) at Week 12, and the proportion of patients achieving endoscopic response (by SES-CD) at Week 12. Secondary efficacy endpoints included clinical response, corticosteroid-free remission, and endoscopic remission (see Table 24 and Table 25).

Onset of clinical response based on CDAI was observed as early as two weeks in Studies CD-1 and CD-2, with a greater proportion of patients achieving clinical response at Week 2 in RINVOQ-treated patients compared with placebo.

In Studies CD-1 and CD-2, reductions in stool frequency and abdominal pain were observed in a greater proportion of patients treated with RINVOQ 45 mg induction regimen compared to placebo at Week 12.

In Studies CD-1 and CD-2, patients treated with RINVOQ experienced a clinically meaningful improvement in fatigue, assessed by change from baseline in FACIT-F score, at Week 12, compared to placebo-treated patients. The effect of RINVOQ to improve fatigue after 12 weeks of induction has not been established.

Maintenance Study (CD-3)

The efficacy analysis for CD-3 (NCT03345823) evaluated 343 patients who responded to 12 weeks of RINVOQ 45 mg once daily induction treatment. Patients were re-randomized to receive a maintenance regimen of either RINVOQ 15 mg or 30 mg once daily or placebo for 52 weeks, representing a total of at least 64 weeks of therapy.

The co-primary endpoints of clinical remission (by CDAI) and endoscopic response (by SES-CD) were assessed at Week 52. Secondary efficacy endpoints included corticosteroid-free clinical remission, maintenance of clinical remission, endoscopic remission, and achieving both clinical and endoscopic remission, at Week 52 (see Table 26).

At Week 52, reductions in stool frequency and abdominal pain were observed in a greater proportion of patients treated with RINVOQ 15 mg and 30 mg compared to placebo.

14.6 Ankylosing Spondylitis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in two randomized, double-blind, multicenter, placebo-controlled trials in patients 18 years of age or older with active ankylosing spondylitis based upon the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 and Patient’s Assessment of Total Back Pain score ≥4.

Trial AS-I (NCT03178487) was a 14-week trial in 187 ankylosing spondylitis patients with an inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs) or intolerance to or contraindication for NSAIDs and had no previous exposure to biologic DMARDs. At baseline, patients had symptoms of ankylosing spondylitis for an average of 14.4 years and approximately 16% of the patients were on a concomitant cDMARD. Patients received RINVOQ 15 mg once daily or placebo. At Week 14, all patients randomized to placebo were switched to RINVOQ 15 mg once daily. The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at Week 14.

Trial AS-II (NCT 04169373) was a 14-week trial in 420 ankylosing spondylitis patients with an inadequate response to 1 or 2 biologic DMARDs. At baseline, patients had symptoms of ankylosing spondylitis for an average of 12.8 years and approximately 31% of the patients were on a concomitant cDMARD. Patients received RINVOQ 15 mg once daily or placebo. At Week 14, all patients randomized to placebo were switched to RINVOQ 15 mg once daily. The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at Week 14.

Clinical Response

In both trials, a significantly greater proportion of patients treated with RINVOQ 15 mg achieved an ASAS40 response compared to placebo at Week 14 (Table 27, Figure 5).

Examination of gender, baseline body mass index (BMI), and baseline hsCRP did not identify differences in response to RINVOQ among these subgroups at Week 14.

Treatment with RINVOQ 15 mg resulted in improvements in the individual components of the ASAS40 response criteria compared to placebo (Table 28).

Figure 5. Percent of Patients Achieving ASAS40 in Trial AS-II*

*Results are based on non-responder imputation in conjunction with multiple imputation.

Other Health-Related Outcomes

In Trial AS-II, patients treated with RINVOQ 15 mg showed significant improvements in health-related quality of life as measured by Ankylosing Spondylitis Quality of Life (ASQoL) compared to placebo at Week 14. In Trial AS-I, improvement in ASQoL compared to placebo was also observed.

Enthesitis

In Trial AS-II, patients with pre-existing enthesitis treated with RINVOQ 15 mg showed significant improvement in enthesitis compared to placebo as measured by change from baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14. In Trial AS-I, improvement in MASES compared to placebo was also observed.

Spinal mobility

In Trial AS-II, patients treated with RINVOQ 15 mg showed significant improvement in spinal mobility compared to placebo as measured by change from baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 14. In Trial AS-I, improvement in BASMI compared to placebo was also observed.

14.7 Non-radiographic Axial Spondyloarthritis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in a randomized, double-blind, multicenter, placebo-controlled trial in patients 18 years of age or older with active non-radiographic axial spondyloarthritis. Trial nr-axSpA (NCT04169373) was a 52-week placebo-controlled trial in 314 patients (of which 313 patients received study treatment) with active non-radiographic axial spondyloarthritis with an inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs) or intolerance to or contraindication for NSAIDs. Patients must have had objective signs of inflammation indicated by elevated C-reactive protein (CRP) (defined as > upper limit of normal), and/or sacroiliitis on magnetic resonance imaging (MRI), and no definitive radiographic evidence of structural damage on sacroiliac joints. Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4, and a Patient's Assessment of Total Back Pain score ≥ 4 based on a 0 – 10 numerical rating scale (NRS) at the Screening and Baseline Visits. At baseline, approximately 29.1% of the patients were on a concomitant cDMARD. 32.9% of the patients had an inadequate response or intolerance to bDMARD therapy. Patients received RINVOQ 15 mg once daily or placebo. The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at Week 14.

Clinical Response

In Trial nr-axSpA, a significantly greater proportion of patients treated with RINVOQ 15 mg achieved an ASAS40 response compared to placebo at Week 14 (Table 29, Figure 6).

Examination of gender, baseline BMI, symptom duration of non-radiographic axial spondyloarthritis, baseline hsCRP, MRI sacroiliitis, and prior use of bDMARDs did not identify differences in response to RINVOQ among these subgroups at Week 14.

Treatment with RINVOQ 15 mg resulted in improvements in the individual components of the ASAS40 response criteria compared to placebo (Table 30).

Figure 6. Percent of Patients Achieving ASAS40*

*Results are based on non-responder imputation in conjunction with multiple imputation.

Other Health-Related Outcomes

Patients treated with RINVOQ 15 mg showed significant improvements in health-related quality of life as measured by Ankylosing Spondylitis Quality of Life (ASQoL) compared to placebo at Week 14.