Highlights

WARNING: Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis

See full prescribing information for complete boxed warning.

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Boxed warning

WARNING: Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis

Serious infections. Patients treated with upadacitinib are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt upadacitinib until the infection is controlled.

Reported infections include:

The risks and benefits of treatment with upadacitinib should be carefully considered before initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection before initiating therapy.

Mortality. In a large, randomized, postmarketing safety study in patients with rheumatoid arthritis who are 50 years of age and older with at least one cardiovascular risk factor comparing another Janus kinase inhibitor to tumor necrosis factor blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor.

Malignancies. Lymphoma and other malignancies have been observed in patients treated with upadacitinib. In patients with rheumatoid arthritis treated with another JAK inhibitor, a higher rate of malignancies (excluding nonmelanoma skin cancer) was observed when compared with TNF blockers. Patients who are current or past smokers are at an additional increased risk.

Major adverse cardiovascular events. In patients with rheumatoid arthritis who are 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. Patients who are current or past smokers are at an additional increased risk. Discontinue upadacitinib in patients who have experienced a myocardial infarction or stroke.

Thrombosis. Thromboses, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including upadacitinib. Many of these adverse events were serious, and some resulted in death. In patients with rheumatoid arthritis who are 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid upadacitinib in patients at risk. Patients with symptoms of thrombosis should discontinue upadacitinib and be promptly evaluated.

Indications and usage

Rheumatoid arthritis. Upadacitinib 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. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

Psoriatic arthritis. Upadacitinib is indicated for the treatment of adults and pediatric patients 2 years of age and older with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

Limitations of use. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

Atopic dermatitis. Upadacitinib 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 is inadvisable.

Limitations of use. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological immunomodulators, or with other immunosuppressants.

Ulcerative colitis. Upadacitinib 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. Upadacitinib 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.

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

Limitations of use. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological therapies for Crohn disease, or with potent immunosuppressants such as azathioprine and cyclosporine.

Ankylosing spondylitis. Upadacitinib 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. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

Non-radiographic axial spondyloarthritis. Upadacitinib 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. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

Polyarticular juvenile idiopathic arthritis. Upadacitinib is indicated for the treatment of patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

Limitations of use. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

Giant cell arteritis. Upadacitinib is indicated for the treatment of adults with giant cell arteritis.

Limitations of use. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

Dosage and administration

Recommended evaluations and immunizations before treatment initiation

Before upadacitinib treatment initiation, consider performing the following evaluations:

Update immunizations according to current immunization guidelines.

Important administration instructions

Recommended dosage in rheumatoid arthritis

The recommended dosage of upadacitinib tablets is 15 mg once daily.

Recommended dosage in psoriatic arthritis

Pediatric patients between 2 and 18 years of age. The recommended dosage is based on body weight (Table 1).

Table 1. Upadacitinib Dosage for Pediatric Patients 2 Years to Less Than 18 Years of Age with Psoriatic Arthritis

Upadacitinib oral solution is not substitutable with upadacitinib extended-release tablets. Changes between upadacitinib oral solution and upadacitinib extended-release tablets should be made by the health care provider.

Adults 18 years of age and older. The recommended dosage of upadacitinib tablets is 15 mg once daily.

Recommended dosage in atopic dermatitis

Pediatric patients 12 years of age and older weighing at least 40 kg and adults younger than 65 years of age. Initiate treatment with upadacitinib 15 mg tablets once daily. If an adequate response is not achieved, consider increasing the dosage to 30 mg once daily. Discontinue upadacitinib tablets if an adequate response is not achieved with the 30 mg dose. Use the lowest effective dose needed to maintain response.

Adults 65 years of age and older. The recommended dosage of upadacitinib tablets is 15 mg once daily.

Recommended dosage in ulcerative colitis

Adult patients: induction. The recommended induction dosage of upadacitinib tablets is 45 mg once daily for 8 weeks.

Adult patients: maintenance. The recommended dosage of upadacitinib tablets 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 upadacitinib tablets if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response.

Recommended dosage in Crohn disease

Adult patients: induction. The recommended induction dosage of upadacitinib tablets is 45 mg once daily for 12 weeks.

Adult patients: maintenance. The recommended dosage of upadacitinib tablets 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 upadacitinib tablets if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response.

Recommended dosage in ankylosing spondylitis

The recommended dosage of upadacitinib tablets is 15 mg once daily.

Recommended dosage in nonradiographic axial spondyloarthritis

The recommended dosage of upadacitinib tablets is 15 mg once daily.

Recommended dosage in polyarticular juvenile idiopathic arthritis

The recommended dosage is based on body weight (Table 2).

Table 2. Upadacitinib Dosage for Patients 2 Years and Older with Polyarticular Juvenile Idiopathic Arthritis

Upadacitinib oral solution is not substitutable with upadacitinib extended-release tablets. Changes between upadacitinib oral solution and upadacitinib extended-release tablets should be made by the health care provider.

Recommended dosage in giant cell arteritis

The recommended dosage of upadacitinib tablets is 15 mg once daily in combination with a tapering course of corticosteroids.

Upadacitinib 15 mg tablets once daily can be used as monotherapy following discontinuation of corticosteroids.

Recommended dosage in patients with renal impairment or hepatic impairment

Renal impairment.

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, and giant cell arteritis.

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

Atopic dermatitis.

For patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to < 30 mL/min/1.73m²), the recommended dosage of upadacitinib tablets is 15 mg once daily.

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

Upadacitinib is not recommended for use in patients with end-stage renal disease (eGFR < 15 mL/min/1.73m²).

Ulcerative colitis.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m²), the recommended dosage of upadacitinib tablets 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).

Upadacitinib is not recommended for use in patients with end-stage renal disease (eGFR < 15 mL/min/1.73m²).

Crohn disease.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m²), the recommended dosage of upadacitinib tablets 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).

Upadacitinib is not recommended for use in patients with end-stage renal disease (eGFR < 15 mL/min/1.73m²).

Hepatic impairment.

Upadacitinib is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

Rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, and giant cell arteritis.

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

Ulcerative colitis.

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

Induction: 30 mg once daily for 8 weeks

Maintenance: 15 mg once daily

Crohn disease.

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

Induction: 30 mg once daily for 12 weeks

Maintenance: 15 mg once daily

Dosage modifications due to drug interactions.

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, and giant cell arteritis.

No dosage adjustment is needed in patients receiving strong CYP3A4 inhibitors.

Atopic dermatitis.

The recommended dosage of upadacitinib tablets in patients receiving strong CYP3A4 inhibitors is 15 mg once daily.

Ulcerative colitis.

The recommended dosage of upadacitinib tablets in patients with ulcerative colitis receiving strong CYP3A4 inhibitors:

Induction: 30 mg once daily for 8 weeks

Maintenance: 15 mg once daily

Crohn disease.

The recommended dosage of upadacitinib tablets in patients with Crohn disease receiving strong CYP3A4 inhibitors:

Induction: 30 mg once daily for 12 weeks

Maintenance: 15 mg once daily

Dosage interruption

Infections. If a patient develops a serious infection, including serious opportunistic infection, interrupt upadacitinib treatment until the infection is controlled.

Laboratory abnormalities. Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 3.

Table 3. Recommended Dosage Interruptions for Laboratory Abnormalities

Dosage forms and strengths

Upadacitinib extended-release tablets:

Upadacitinib oral solution:

Contraindications

Upadacitinib is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients.

Warnings and precautions

Serious infections

Serious and sometimes fatal infections have been reported in patients receiving upadacitinib tablets. The most frequent serious infections reported with upadacitinib tablets included pneumonia and cellulitis. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral or esophageal candidiasis, and cryptococcosis were reported with upadacitinib tablets. A higher rate of serious infections was observed with upadacitinib 30 mg tablets compared to 15 mg tablets.

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

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

A patient who develops a new infection during treatment with upadacitinib 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 upadacitinib should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib may be resumed once the infection is controlled.

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

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

During upadacitinib use, monitor patients for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection before initiating therapy.

Viral reactivation. Viral reactivation, including cases of herpes virus reactivation (eg, herpes zoster) and hepatitis B virus reactivation, was reported in clinical trials with upadacitinib tablets. The risk of herpes zoster appears to be higher in patients treated with upadacitinib tablets in Japan. If a patient develops herpes zoster, consider temporarily interrupting upadacitinib 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 upadacitinib. 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 upadacitinib tablets. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.

Mortality

In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with rheumatoid arthritis who are 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 before initiating or continuing therapy with upadacitinib.

Malignancy and lymphoproliferative disorders

Malignancies, including lymphomas, were observed in clinical trials of upadacitinib tablets.

In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with rheumatoid arthritis, a higher rate of malignancies (excluding nonmelanoma skin cancer) 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 before initiating or continuing therapy with upadacitinib, particularly in patients with a known malignancy (other than a successfully treated nonmelanoma skin cancer), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

Nonmelanoma skin cancer. Nonmelanoma skin cancers have been reported in patients treated with upadacitinib tablets. 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.

Major adverse cardiovascular events

In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with rheumatoid arthritis who are 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events 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 an additional increased risk.

Consider the benefits and risks for the individual patient before initiating or continuing therapy with upadacitinib, 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 upadacitinib in patients who have experienced a myocardial infarction or stroke.

Thrombosis

Thromboses, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including upadacitinib tablets. Many of these adverse events were serious, and some resulted in death.

In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with rheumatoid arthritis who are 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, deep venous thrombosis, and pulmonary embolism were observed compared to those treated with TNF blockers.

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

Hypersensitivity reactions

Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving upadacitinib tablets in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue upadacitinib and institute appropriate therapy.

Gastrointestinal perforations

Gastrointestinal perforations have been reported in clinical trials with upadacitinib tablets.

Monitor upadacitinib-treated patients who may be at risk for gastrointestinal perforation (eg, 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.

Laboratory abnormalities

Neutropenia. Treatment with upadacitinib 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 upadacitinib initiation and interrupt upadacitinib treatment in patients with a low neutrophil count (ie, ANC less than 1000 cells/mm3).

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

Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid upadacitinib initiation or interrupt upadacitinib treatment in patients with a low lymphocyte count (ie, less than 500 cells/mm3).

Anemia. Decreases in hemoglobin levels to less than 8 g/dL were reported in patients treated with upadacitinib in clinical trials.

Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid upadacitinib initiation or interrupt upadacitinib treatment in patients with a low hemoglobin level (ie, less than 8 g/dL).

Lipids. Treatment with upadacitinib was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Elevations in LDL cholesterol decreased to 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 upadacitinib was associated with an 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, upadacitinib should be interrupted until this diagnosis is excluded.

Embryo-fetal toxicity

Based on findings in animal studies, upadacitinib 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 before starting treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with upadacitinib and for 4 weeks following completion of therapy.

Vaccinations

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

Medication residue in stool

Reports of medication residue in stool or ostomy output have occurred in patients taking upadacitinib. Most reports described anatomic (eg, 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.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

Clinical trials experience

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

Adverse reactions in patients with rheumatoid arthritis. A total of 3833 adult patients with rheumatoid arthritis were treated with upadacitinib 15 mg or 30 mg tablets once daily in the Phase 3 clinical trials, of whom 2806 were exposed for at least 1 year.

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

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

Table 4. Adverse Reactions Reported in ≥ 1% of Rheumatoid Arthritis Patients Treated with Upadacitinib 15 mg Tablets in Placebo-Controlled Trials

Other adverse reactions reported in less than 1% of patients in the upadacitinib 15 mg tablets 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 upadacitinib 15 mg tablets (n=1035). Trials RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), upadacitinib 15 mg tablets (n=385), and 30 mg tablets (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 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), upadacitinib 15 mg tablets (n=534), and 30 mg tablets (n=529).

Twelve-month exposure dataset: Trials RA-I, II, III, and V were integrated to represent the long-term safety of upadacitinib 15 mg tablets (n=1213) and 30 mg tablets (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 upadacitinib 15 mg tablets. 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 upadacitinib 15 mg tablets, and 126 patients (180.3 per 100 patient-years) treated with 30 mg tablets.

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 upadacitinib 15 mg tablets monotherapy, and 128 patients (115.1 per 100 patient-years) treated with upadacitinib 30 mg tablets monotherapy.

Twelve-month exposure dataset: Infections were reported in 615 patients (83.8 per 100 patient-years) treated with upadacitinib 15 mg tablets and 674 patients (99.7 per 100 patient-years) treated with 30 mg tablets.

Serious infections.

Placebo-controlled trials: In RA-III, RA-IV, and RA-V, serious infections were reported in six patients (2.3 per 100 patient-years) treated with placebo, and 12 patients (4.6 per 100 patient-years) treated with upadacitinib 15 mg tablets. In RA-III and RA-V, serious infections were reported in one patient (1.2 per 100 patient-years) treated with placebo, two patients (2.3 per 100 patient-years) treated with upadacitinib 15 mg tablets, and seven patients (8.2 per 100 patient-years) treated with 30 mg tablets.

MTX-controlled trials: Serious infections were reported in two patients (1.6 per 100 patient-years) treated with MTX monotherapy, three patients (2.4 per 100 patient-years) treated with upadacitinib 15 mg tablets monotherapy, and eight patients (6.4 per 100 patient-years) treated with upadacitinib 30 mg tablets monotherapy.

Twelve-month exposure dataset: Serious infections were reported in 38 patients (3.5 per 100 patient-years) treated with upadacitinib 15 mg tablets and 59 patients (5.6 per 100 patient-years) treated with upadacitinib 30 mg tablets.

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, upadacitinib 15 mg tablets, and 30 mg tablets groups. In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, upadacitinib 15 mg tablets monotherapy, and 30 mg tablet monotherapy groups.

Twelve-month exposure dataset: Active tuberculosis was reported for two patients treated with upadacitinib 15 mg tablets and one patient treated with 30 mg tablets. 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 three patients (1.2 per 100 patient-years) treated with placebo, and five patients (1.9 per 100 patient-years) treated with upadacitinib 15 mg tablets. In RA-III and RA-V, opportunistic infections were reported in one patient (1.2 per 100 patient-years) treated with placebo, two patients (2.3 per 100 patient-years) treated with upadacitinib 15 mg tablets, and six patients (7.1 per 100 patient-years) treated with 30 mg tablets.

MTX-controlled trials: Opportunistic infections were reported in one patient (0.8 per 100 patient-years) treated with MTX monotherapy, zero patients treated with upadacitinib 15 mg tablets monotherapy, and four patients (3.2 per 100 patient-years) treated with upadacitinib 30 mg tablets monotherapy.

Twelve-month exposure dataset: Opportunistic infections were reported in seven patients (0.6 per 100 patient-years) treated with upadacitinib 15 mg tablets and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg tablets.

Malignancies.

Placebo-controlled trials: In RA-III, RA-IV, and RA-V, malignancies excluding nonmelanoma skin cancer were reported in one patient (0.4 per 100 patient-years) treated with placebo, and one patient (0.4 per 100 patient-years) treated with upadacitinib 15 mg tablets. In RA-III and RA-V, malignancies excluding nonmelanoma skin cancer were reported in zero patients treated with placebo, one patient (1.1 per 100 patient-years) treated with upadacitinib 15 mg tablets, and three patients (3.5 per 100 patient-years) treated with upadacitinib 30 mg tablets.

MTX-controlled trials: Malignancies excluding nonmelanoma skin cancer were reported in one patient (0.8 per 100 patient-years) treated with MTX monotherapy, three patients (2.4 per 100 patient-years) treated with upadacitinib 15 mg tablets monotherapy, and zero patients treated with upadacitinib 30 mg tablets monotherapy.

Twelve-month exposure dataset: Malignancies excluding nonmelanoma skin cancer were reported in 13 patients (1.2 per 100 patient-years) treated with upadacitinib 15 mg tablets and 14 patients (1.3 per 100 patient-years) treated with upadacitinib 30 mg tablets.

Gastrointestinal perforations

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

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

Twelve-month exposure dataset: Gastrointestinal perforations were reported in one patient treated with upadacitinib 15 mg tablets and four patients treated with 30 mg tablets.

Thrombosis

Placebo-controlled trials: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in one patient treated with placebo, and one patient treated with upadacitinib 15 mg tablets. In RA-V, venous thrombosis was observed in one patient treated with upadacitinib 15 mg tablets. 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 zero patients treated with MTX monotherapy, one patient treated with upadacitinib 15 mg tablets monotherapy, and zero patients treated with upadacitinib 30 mg monotherapy through Week 14. In RA-II, no cases of arterial thrombosis were observed through 12 or 14 weeks. In RA-I, venous thrombosis was observed in one patient treated with MTX, zero patients treated with upadacitinib 15 mg tablets, and one patient treated with upadacitinib 30 mg through Week 24. In RA-I, arterial thrombosis was observed in one patient treated with upadacitinib 30 mg through Week 24.

Twelve-month exposure dataset: Venous thrombosis events were reported in five patients (0.5 per 100 patient-years) treated with upadacitinib 15 mg tablets and four patients (0.4 per 100 patient-years) treated with upadacitinib 30 mg tablets. Arterial thrombosis events were reported in 0 patients treated with upadacitinib 15 mg tablets and two patients (0.2 per 100 patient-years) treated with upadacitinib 30 mg tablets.

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 three or more times the upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with upadacitinib 15 mg tablets, and in 1.5% and 0.7% of patients treated with placebo, respectively. In RA-III and RA-V, ALT and AST elevations three or more times ULN in at least one measurement were observed in 0.8% and 1.0% of patients treated with upadacitinib 15 mg tablets, 1.0% and 0% of patients treated with upadacitinib 30 mg tablets, 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 three or more times the ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with upadacitinib 15 mg tablets, 1.7% and 1.3% of patients treated with upadacitinib 30 mg tablets, 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 upadacitinib 15 mg and 30 mg tablets, respectively, are summarized below:

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 more than five times the ULN were reported in 1.0% and 0.3% of patients over 12/14 weeks in the upadacitinib 15 mg tablets and placebo groups, respectively. Most elevations more than five times the ULN were transient and did not require treatment discontinuation. In RA-III and RA-V, CPK elevations more than five times the ULN were observed in 0.3% of patients treated with placebo, 1.6% of patients treated with upadacitinib 15 mg tablets, and none in patients treated with 30 mg tablets.

Neutropenia. In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12 or 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 upadacitinib 15 mg tablets 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 upadacitinib 15 mg tablets, and 2.4% of patients treated with 30 mg tablets. 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 upadacitinib 15 mg tablets 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 upadacitinib 15 mg tablets, and 2.4% of patients treated with 30 mg tablets.

Anemia. In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12 or 14 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in <0.1% of patients in both the upadacitinib 15 mg tablets 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 upadacitinib 15 mg and 30 mg tablets.

Adverse reactions in patients with psoriatic arthritis. A total of 1827 adult patients with psoriatic arthritis were treated with upadacitinib 15 mg or 30 mg tablets once daily in clinical trials, representing 1639.2 patient-years of exposure, of whom 722 were exposed to upadacitinib for at least 1 year. In the two Phase 3 trials, 907 patients received at least one dose of upadacitinib 15 mg tablets, of whom 359 were exposed for at least 1 year.

Two placebo-controlled trials were integrated (640 patients on upadacitinib 15 mg tablets once daily and 635 patients on placebo) to evaluate the safety of upadacitinib 15 mg tablets 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 upadacitinib 15 mg tablets 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 upadacitinib 15 mg tablets and 0.8% and 1.3%, respectively, with placebo. A higher incidence of acne and bronchitis was also observed in patients treated with upadacitinib 15 mg tablets (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 upadacitinib in patients with moderate to severe atopic dermatitis. The majority of patients were White (68%) and male (57%). The mean age was 34 years (ranging from 12 to 75 years), and 13% of the patients were between 12 and 18 years of age. In these four trials, 2612 patients were treated with upadacitinib 15 mg or 30 mg tablets orally once daily, with or without concomitant topical corticosteroids.

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

Trials AD-1, AD-2, and AD-4 compared the safety of upadacitinib tablets monotherapy to placebo through Week 16. Trial AD-3 compared the safety of upadacitinib tablets + topical corticosteroids to placebo + topical corticosteroids through Week 16.

Weeks 0 to 16 (Trials AD-1 to AD-4). In upadacitinib tablets trials with and without topical corticosteroids (Trials AD-1, 2, 3, and 4) through Week 16, the proportions of patients who discontinued treatment because of adverse reactions in the upadacitinib 15 mg tablets, 30 mg tablets, and placebo groups were 2.3%, 2.9% and 3.8%, respectively. Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% in the upadacitinib 15 mg or 30 mg tablet groups during the first 16 weeks of treatment.

Table 5. Adverse Reactions Reported in ≥ 1% of Patients with Atopic Dermatitis Treated with Upadacitinib 15 mg or 30 mg Tablets

Other adverse reactions reported in less than 1% of patients in the upadacitinib 15 mg or 30 mg tablets 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 upadacitinib tablets through Week 52 was generally consistent with the safety profile observed at Week 16.

Overall, the safety profile observed in patients with atopic dermatitis treated with upadacitinib tablets was similar to the safety profile in patients with rheumatoid arthritis. Other specific adverse reactions that were reported in patients with atopic dermatitis included eczema herpeticum/Kaposi’s varicelliform eruption.

Eczema herpeticum/kaposi’s varicelliform eruption.

Placebo-controlled period (16 weeks): Eczema herpeticum was reported in four patients (1.6 per 100 patient-years) treated with placebo, six patients (2.2 per 100 patient-years) treated with upadacitinib 15 mg tablets, and seven patients (2.6 per 100 patient-years) treated with upadacitinib 30 mg tablets.

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

Adverse reactions in patients with ulcerative colitis. Upadacitinib 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.

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 upadacitinib 45 mg tablets once daily.

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

Adverse reactions reported in ≥2% of patients in any treatment arm in the induction and maintenance studies are shown in Tables 6 and 7, respectively.

Table 6. Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with Upadacitinib 45 mg in Placebo-Controlled Induction Studies (UC-1, UC-2, and UC-4)

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

Table 7. Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with Upadacitinib 15 mg or 30 mg Tablets in the Placebo-Controlled Maintenance Study (UC-3)1

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

The safety profile of upadacitinib 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 upadacitinib was generally similar to the safety profile in patients with rheumatoid arthritis and atopic dermatitis.

Specific adverse reactions

Serious infections

Induction studies: In UC-1, UC-2, and UC-4, serious infections were reported in five patients (8.4 per 100 patient-years) treated with placebo and nine patients (8.4 per 100 patient-years) treated with upadacitinib 45 mg tablets through 8 weeks.

Placebo-controlled maintenance study: In UC-3, serious infections were reported in eight patients (5.9 events per 100 patient-years) treated with placebo, nine patients (5.0 events per 100 patient-years) treated with upadacitinib 15 mg tablets, and eight patients (3.7 events per 100 patient-years) treated with upadacitinib 30 mg tablets through 52 weeks.

Laboratory abnormalities

Hepatic transaminase elevations

In studies UC-1, UC-2, and UC-4, elevations of ALT to three or more times the ULN in at least one measurement were observed in 1.5% of patients treated with upadacitinib 45 mg tablets, and 0% of patients treated with placebo for 8 weeks. AST elevations to three or more times the ULN occurred in 1.5% of patients treated with upadacitinib 45 mg tablets, and 0.3% of patients treated with placebo. Elevations of ALT to five or more times the ULN occurred in 0.4% of patients treated with upadacitinib 45 mg tablets and 0% of patients treated with placebo.

In UC-3, elevations of ALT to three or more times the ULN in at least one measurement were observed in 4.4% of patients treated with upadacitinib 30 mg tablets, 2% of patients treated with upadacitinib 15 mg tablets, and 1.2% of patients treated with placebo for 52 weeks. Elevations of AST to three or more times the ULN in at least one measurement were observed in 2% of patients treated with upadacitinib 30 mg tablets, 1.6% of patients treated with upadacitinib 15 mg tablets, and 0.4% of patients treated with placebo. Elevations of ALT to five or more times the ULN were observed in 1.2% of patients treated with 30 mg, 0.4% of patients treated with 15 mg, and 0.4% of patients treated with placebo.

Overall, laboratory abnormalities observed in patients with ulcerative colitis treated with upadacitinib tablets were similar to those described in patients with rheumatoid arthritis.

Adverse reactions in patients with Crohn disease. Upadacitinib was studied up to 12 weeks in patients with moderately to severely active Crohn disease 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 period.

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

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

Overall, the safety profile observed in patients with Crohn disease treated with upadacitinib tablets was consistent with the known safety profile for upadacitinib tablets in other indications.

Adverse reactions reported in ≥2% of patients treated with upadacitinib tablets and at a higher rate than placebo in the induction and maintenance studies are shown in Tables 8 and 9, respectively.

Table 8. Adverse Reactions Reported in ≥2% of Patients with Crohn Disease Treated with Upadacitinib Tablets 45 mg in Placebo-Controlled Induction Studies (CD-1 and CD-2)

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

Table 9. Adverse Reactions Reported in ≥2% of Patients with Crohn Disease Treated with Upadacitinib Tablets 15 mg or 30 mg in the Placebo-Controlled Maintenance Study (CD-3)1

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

The safety profile of upadacitinib tablets 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 six patients (eight per 100 patient-years) treated with placebo and 13 patients (nine per 100 patient-years) treated with upadacitinib 45 mg tablets through 12 weeks of the placebo-controlled period.

Maintenance study/long-term extension: In the long-term placebo-controlled period, serious infections were reported in 10 patients (seven per 100 patient-years) treated with placebo, seven patients (four per 100 patient-years) treated with upadacitinib 15 mg tablets, and 13 patients (six per 100 patient-years) treated with upadacitinib 30 mg tablets.

Gastrointestinal perforations. Induction Studies: During the induction studies in all patients treated with upadacitinib 45 mg tablets (N=938), gastrointestinal perforation was reported in four patients (two 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 one patient (one per 100 patient-years) treated with upadacitinib 45 mg tablets (N=674) through 12 weeks.

Maintenance study/long-term extension: In the long-term placebo-controlled period, gastrointestinal perforation was reported in one patient (one per 100 patient-years) treated with placebo, one patient (<one per 100 patient-years) treated with upadacitinib 15 mg tablets, and one patient (<one per 100 patient-years) treated with upadacitinib 30 mg tablets.

Patients who received placebo or upadacitinib 15 mg tablets for maintenance therapy and lost response were treated with rescue upadacitinib 30 mg tablets (N=336). Among these patients, gastrointestinal perforation was reported in three patients (one 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 upadacitinib 15 mg tablets in the two clinical trials, representing 577.3 patient-years of exposure, of whom 220 were exposed to upadacitinib 15 mg tablets for at least 1 year.

Overall, the safety profile observed in patients with active ankylosing spondylitis treated with upadacitinib 15 mg tablets 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 upadacitinib 15 mg tablets and 2.1% with placebo. During the 14-week placebo-controlled period in Trial AS-II, the frequency of headache was 3.3% with upadacitinib 15 mg tablets and 1.4% with placebo.

Adverse reactions in patients with non-radiographic axial spondyloarthritis. A total of 187 patients with nonradiographic axial spondyloarthritis were treated with upadacitinib 15 mg tablets in the clinical trial, representing 116.6 patient-years of exposure, of whom 31 were exposed to upadacitinib 15 mg tablets for at least 1 year.

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

Adverse reactions in patients with polyarticular juvenile idiopathic arthritis. A total of 83 pediatric patients with juvenile idiopathic arthritis with active polyarthritis were treated with upadacitinib in the clinical trial, representing 123.7 patient-years of exposure, of whom 48 were exposed to upadacitinib for at least 1 year.

Overall, the safety profile observed in pediatric patients with juvenile idiopathic arthritis with active polyarthritis treated with upadacitinib was consistent with the known safety profile of upadacitinib tablets.

Adverse reactions in patients with giant cell arteritis. In the Phase 3 study, 209 patients with giant cell arteritis received at least one dose of upadacitinib 15 mg tablets, of whom 122 were exposed for at least 1 year during the 52-week placebo-controlled period. The safety profile observed in patients with giant cell arteritis was generally consistent with the known safety profile for upadacitinib tablets.

Table 10. Adverse Reactions Reported in ≥ 5% of Patients with Giant Cell Arteritis Treated with Upadacitinib Tablets 15 mg in the Placebo-controlled Study

Specific adverse reactions

Opportunistic infections (excluding tuberculosis and herpes zoster). In the 52-week placebo-controlled period, opportunistic infections were reported in one patient (1.1 per 100 patient-years) treated with placebo and four patients (2.3 per 100 patient-years) treated with upadacitinib 15 mg tablets.

Thrombosis. In the 52-week placebo-controlled period, venous thromboembolic events (pulmonary embolism or deep vein thrombosis) were observed in four patients (4.3 per 100 patient-years) treated with placebo and seven patients (3.9 per 100 patient-years) treated with upadacitinib 15 mg tablets. Events of arterial thrombosis were observed in two patients (1.1 per 100 patient-years) treated with upadacitinib 15 mg tablets and zero patients treated with placebo.

Drug interactions

Strong CYP3A4 inhibitors. Upadacitinib exposure is increased when it is co-administered with a strong CYP3A4 inhibitor (such as ketoconazole, clarithromycin, and grapefruit), which may increase the risk of adverse reactions. Monitor patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondylarthritis, polyarticular juvenile idiopathic arthritis, or giant cell arteritis closely for adverse reactions when co-administering upadacitinib with strong CYP3A4 inhibitors. Food or drink containing grapefruit should be avoided during treatment with upadacitinib.

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

For patients with ulcerative colitis or Crohn disease taking strong CYP3A4 inhibitors, reduce the upadacitinib tablets induction dosage to 30 mg once daily. The recommended maintenance dosage is 15 mg once daily.

Strong CYP3A4 inducers. Upadacitinib exposure is decreased when it is co-administered with strong CYP3A4 inducers (such as rifampin), which may lead to reduced therapeutic effect. Coadministration of upadacitinib with strong CYP3A4 inducers is not recommended.

Use in specific populations

Pregnancy

Pregnancy surveillance program. There is a pregnancy surveillance program for upadacitinib that monitors pregnancy outcomes in women exposed to upadacitinib. If upadacitinib exposure occurs during pregnancy, healthcare providers or patients should report the pregnancy by calling 1-800-633-9110.

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

In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the 15 mg tablet dose, 0.8 and 7.6 times the 30 mg tablet dose, and 0.6 and 5.6 times the maximum recommended human dose (MRHD) of 45 mg (on an AUC basis) resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib during organogenesis at exposures approximately 0.29 and 2.2 times the 15 mg dose, 0.15 times and 1.1 times the 30 mg dose, and at 0.11 and 0.82 times the MRHD (on an AUC basis). In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately three 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 defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriages are 2% to 4% and 15% to 20%, respectively.

Clinical considerations.

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

Data.

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

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

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

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

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 upadacitinib, 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 to 8. Drug exposure was approximately 30-fold greater in milk than in maternal plasma based on AUC_0-t values. Approximately 97% of drug-related material in milk was the parent drug.

Females and males of reproductive potential

Pregnancy testing. Verify the pregnancy status of females of reproductive potential before starting treatment with upadacitinib.

Contraception in females. Based on animal studies, upadacitinib may cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with upadacitinib and for 4 weeks after the final dose.

Pediatric use

Ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, and Crohn disease. The safety and effectiveness of upadacitinib in pediatric patients with ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, or Crohn disease have not been established.

Polyarticular juvenile idiopathic arthritis and psoriatic arthritis. The safety and effectiveness of upadacitinib in pediatric patients between 2 and 18 years of age with polyarticular juvenile idiopathic arthritis and psoriatic arthritis have been established.

The use of upadacitinib in these age groups is supported by evidence from well-controlled studies of upadacitinib tablets in adults with rheumatoid arthritis and psoriatic arthritis, pharmacokinetic data from adult patients with rheumatoid arthritis and psoriatic arthritis and 51 pediatric patients with juvenile idiopathic arthritis with active polyarthritis, and safety data from 83 pediatric patients between 2 and 18 years of age with juvenile idiopathic arthritis with active polyarthritis. Upadacitinib plasma exposures in pediatric patients with polyarticular juvenile idiopathic arthritis and psoriatic arthritis at the recommended dosage are predicted to be comparable to those observed in adults with rheumatoid arthritis and psoriatic arthritis based on population pharmacokinetic modeling and simulation.

The safety and effectiveness of upadacitinib in pediatric patients less than 2 years of age with polyarticular juvenile idiopathic arthritis or psoriatic arthritis have not been established.

Atopic dermatitis. The safety and effectiveness of upadacitinib tablets 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 upadacitinib 15 mg tablets (N=114), 30 mg tablets (N=114), or matching placebo (N=116) in monotherapy or combination with topical corticosteroids. Efficacy was consistent between the pediatric patients and adults. The adverse reaction profile in the pediatric patients was similar to that of adults.

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

The safety and effectiveness of upadacitinib oral solution in pediatric patients with atopic dermatitis have not been established.

Geriatric use

Rheumatoid arthritis and psoriatic arthritis. Of the 4381 patients treated in the five clinical trials, a total of 906 patients with rheumatoid arthritis were 65 years of age or older, including 146 patients who were 75 years or older. Of the 1827 patients treated in the two psoriatic arthritis Phase 3 clinical trials, a total of 274 patients were 65 years of age or older, including 34 patients 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 six 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 upadacitinib tablets 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 disease. Of the 1021 patients who were treated in the controlled induction clinical trials, a total of 39 patients with Crohn disease were 65 years of age or older, and no patients were 75 years of age or older. Clinical studies of upadacitinib tablets did not include sufficient numbers of patients 65 years of age and older with Crohn 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 upadacitinib tablets 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.

Nonradiographic axial spondyloarthritis. Of the 313 patients treated in a Phase 3 clinical trial, a total of nine patients with non-radiographic axial spondyloarthritis were 65 years and older. Clinical studies of upadacitinib tablets 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.

Renal impairment

For patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, or giant cell arteritis 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 of upadacitinib tablets 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 disease, the recommended dosage of upadacitinib tablets 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.

Upadacitinib 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 disease with end-stage renal disease is not recommended.

Hepatic impairment

The use of upadacitinib has not been studied in patients with severe hepatic impairment (Child Pugh C), and is, therefore, not recommended.

For patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, or giant cell arteritis, 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 disease, the recommended dosage of upadacitinib tablets for mild to moderate hepatic impairment is 30 mg once daily for induction and 15 mg once daily for maintenance.

Clinical pharmacology

Mechanism of action

Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that 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 (eg, 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.

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 the 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 that 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.

Pharmacokinetics

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. After a single dose administration of upadacitinib 15 mg, 30 mg, and 45 mg tablets under fasting condition in healthy subjects, mean C_max was 31.6 ng/mL, 71.8 ng/mL, and 90.7 ng/mL, respectively, and mean AUC_inf was 265 ng·h/mL, 543 ng·h/mL, and 752 ng·h/mL, respectively. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after once daily administration. Following the administration of the recommended pediatric dosage (Table 1, Table 2) in patients with polyarticular juvenile idiopathic arthritis and psoriatic arthritis, the mean steady-state C_max is predicted to be 47.6 ng/mL, and the mean steady-state AUC0-24 is predicted to be 342 ng·h/mL. Upadacitinib pharmacokinetics are comparable between patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn disease, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and giant cell arteritis.

Upadacitinib tablets and upadacitinib oral solution are not bioequivalent; therefore, the two dosage forms are not interchangeable on a milligram-per-milligram basis.

Absorption.

Following oral administration of upadacitinib extended-release tablets, upadacitinib is absorbed with a median T_max of 2 to 4 hours. Following oral administration of 6 mg of upadacitinib oral solution, upadacitinib is absorbed with a median T_max of 1 hour.

Coadministration of upadacitinib tablets with a high-fat/high-calorie meal had no clinically relevant effect on upadacitinib exposures (increased AUC_inf by 29% and C_max by 39% to 60%). Coadministration of upadacitinib oral solution with food is not expected to have a clinically relevant effect on upadacitinib exposure.

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 mainly by 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 the upadacitinib dose was excreted as metabolites. Upadacitinib’s mean terminal elimination half-life ranged from 8 to 14 hours.

Specific populations.

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

Pediatric patients. In pediatric patients with juvenile idiopathic arthritis with active polyarthritis, upadacitinib clearance increased with increasing body weight. Age (over the range of between 2 and 18 years) had no additional effect on upadacitinib pharmacokinetics after accounting for the effect of body weight. Upadacitinib plasma exposures in pediatric patients with polyarticular juvenile idiopathic arthritis and psoriatic arthritis following the recommended pediatric dosage are predicted to be comparable to those observed in adult patients with rheumatoid arthritis and psoriatic arthritis, respectively.

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

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

Patients with renal impairment. Upadacitinib mean AUC_inf after a single dose administration of 15 mg upadacitinib tablets was 18%, 33%, and 44% higher in patients with mild (eGFR 60 to < 90 mL/min/1.73 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 C_max was similar among subjects with normal and impaired renal function. In patients receiving upadacitinib, mild and moderate renal impairment is not expected to have a clinically relevant effect on upadacitinib exposure.

Patients with hepatic impairment. Upadacitinib’s mean AUC_inf after a single dose administration of 15 mg upadacitinib tablets was 28% and 24% higher in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib mean C_max was unchanged in patients with mild hepatic impairment and 43% higher in patients with moderate hepatic impairment compared to subjects with normal liver function. Upadacitinib was not studied in patients with severe hepatic impairment (Child-Pugh C).

Drug interaction studies.

Potential for other drugs to influence the pharmacokinetics of upadacitinib. Upadacitinib is metabolized in vitro by CYP3A4 with a minor contribution from CYP2D6. The effect of co-administered drugs on upadacitinib plasma exposures is provided in Table 11.

Table 11. Change in Pharmacokinetics of Upadacitinib in the Presence of Co-administered Drugs

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

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

Clinical studies indicate that upadacitinib has no clinically relevant effects on the pharmacokinetics of co-administered drugs. Following upadacitinib 30 mg and 45 mg tablets once daily, the effects on each of the CYP enzymes (CYP1A2, CYP3A, CYP2C9, and CYP2C19) were similar between the two doses except for the effect on CYP2D6. Following upadacitinib 30 mg and 45 mg tablets once daily, a weak induction of CYP3A4 was observed. A weak inhibition of CYP2D6 was observed at upadacitinib 45 mg but not at 30 mg. A summary of results from clinical studies that evaluated the effect of upadacitinib on other drugs is provided in Table 12.

Table 12. Change in Pharmacokinetics of Co-administered Drugs or In Vivo Markers of CYP Activity in the Presence of Upadacitinib

Nonclinical toxicology

Carcinogenesis, mutagenesis, and 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 four and 10 times the 15 mg tablet dose, two and five times the 30 mg tablet dose, and 1.6 and four 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 on 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 tablet dose, 11 and 43 times the 30 mg tablet 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 two times the 15 mg dose, 0.9 times the 30 mg dose, and at 0.6 times the MRHD on an AUC basis).

Clinical studies

See the Clinical studies section of the DAILYMED drug label information for clinical study information.

How supplied/storage and handling

How supplied

Upadacitinib extended-release tablets are supplied as:

Upadacitinib oral solution is supplied as:

Storage and handling

Upadacitinib extended-release tablets:

Upadacitinib oral solution:

Patient counseling information

Advise the patient and caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Serious infections. Inform patients that they may be more likely to develop infections when taking upadacitinib. Instruct patients to contact their healthcare provider immediately during treatment if they develop any signs or symptoms of an infection.

Advise patients that the risk of herpes zoster is increased in patients taking upadacitinib and, in some cases, can be serious.

Malignancies. Inform patients that upadacitinib may increase their risk of certain cancers and that periodic skin examinations should be performed while using upadacitinib.

Advise patients that exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen.

Major adverse cardiovascular events. Inform patients that upadacitinib may increase their risk of major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events.

Thrombosis. Inform patients that events of deep venous thrombosis and pulmonary embolism have been reported in clinical trials with upadacitinib. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a deep venous thrombosis or pulmonary embolism.

Hypersensitivity reactions. Advise patients to discontinue upadacitinib and seek immediate medical attention if they develop any signs and symptoms of allergic reactions.

Gastrointestinal perforations. Inform patients that gastrointestinal perforations have been reported in clinical trials with upadacitinib and that risk factors include the use of NSAIDs, corticosteroids, or history of diverticulitis. Instruct patients to seek medical care immediately if they experience a new onset of abdominal pain, fever, chills, nausea, or vomiting.

Retinal detachment. Inform patients that retinal detachment has been reported in clinical trials with upadacitinib. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving upadacitinib.

Laboratory abnormalities. Inform patients that upadacitinib may affect certain lab tests, and that blood tests are required before and during upadacitinib treatment.

Vaccinations. Advise patients to avoid use of live vaccines with upadacitinib. Instruct patients to inform their healthcare practitioner that they are taking upadacitinib before a potential vaccination.

Embryo-fetal toxicity. Advise pregnant women and females of reproductive potential that exposure to upadacitinib during pregnancy may result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential that effective contraception should be used during treatment and for 4 weeks following the final dose of upadacitinib.

Advise women exposed to upadacitinib during pregnancy that there is a pregnancy surveillance program that monitors pregnancy outcomes.

Lactation. Advise women not to breastfeed during treatment with upadacitinib and for 6 days after the last dose.

Administration. Advise patients that upadacitinib tablets are not substitutable with upadacitinib oral solution.

Advise patients not to chew, crush, or split upadacitinib tablets.

For upadacitinib oral solution, instruct patients and caregivers to read and follow the Instructions for Use for proper preparation, administration, storage, and disposal.

Advise patients to avoid food or drink containing grapefruit during treatment with upadacitinib.

Medication residue in stool. Instruct patients to notify their healthcare provider if they repeatedly notice medication residue (eg, intact upadacitinib tablet or fragments) in stool or ostomy output.

Medication guide

See the FDA-approved medication guide section.

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.