upadacitinib: prescribing information – dosing, contraindications, interactions, side effects

Rheumatoid arthritis

RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.

Psoriatic arthritis

RINVOQ is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate.

Polyarticular juvenile idiopathic arthritis

RINVOQ is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (polyarticular rheumatoid factor positive [RF+] or negative [RF-], extended oligoarticular), in patients 2 years of age and older who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate.

Axial spondyloarthritis

Non-radiographic axial spondyloarthritis (nr-axSpA)

RINVOQ is indicated for the treatment of active non-radiographic axial spondyloarthritis in adult patients with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti- inflammatory drugs (NSAIDs).

Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)

RINVOQ is indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.

Giant cell arteritis

RINVOQ is indicated for the treatment of giant cell arteritis in adult patients.

Atopic dermatitis

RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.

Alopecia areata

RINVOQ is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years and older (see section 5.1).

Vitiligo

RINVOQ is indicated for the treatment of non-segmental vitiligo in adults and adolescents 12 years and older who are candidates for systemic therapy.

Ulcerative colitis

RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.

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, lost response or were intolerant to either conventional therapy or a biologic agent.

RINVOQ is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (polyarticular rheumatoid factor positive [RF+] or negative [RF-], extended oligoarticular), in patients 2 years of age and older who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.

Treatment with upadacitinib should be initiated and supervised by physicians experienced in the diagnosis and treatment of conditions for which upadacitinib is indicated.

Posology

Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis

The recommended dose of upadacitinib is 15 mg once daily.

Consideration should be given to discontinuing treatment in patients with axial spondyloarthritis who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Polyarticular juvenile idiopathic arthritis

The recommended dose is based on body weight.

Table 1 Upadacitinib dose for patients with polyarticular juvenile idiopathic arthritis two years of age and older

Patient weight
Dosing regimen
10 to < 20 kg
3 mg (3 ml oral solution) twice daily
20 to < 30 kg
4 mg (4 ml oral solution) twice daily
≥ 30 kg
6 mg (6 ml oral solution) twice daily or
15 mg (one 15 mg tablet) once daily

RINVOQ tablets and RINVOQ oral solution are not bioequivalent. Therefore, the two pharmaceutical forms are not interchangeable on a milligram-per-milligram basis.

Giant cell arteritis

The recommended dose of upadacitinib is 15 mg once daily in combination with a tapering course of corticosteroids. Upadacitinib monotherapy should not be used for the treatment of acute relapses (see section 4.4).

Based upon the chronic nature of giant cell arteritis, upadacitinib 15 mg once daily can be continued as monotherapy following discontinuation of corticosteroids.

Atopic dermatitis

The recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.

- A dose of 15 mg is recommended for patients at higher risk of venous thromboembolism (VTE), major adverse cardiovascular events (MACE) and malignancy (see section 4.4).
- A dose of 30 mg once daily may be appropriate for patients with high disease burden who are not at higher risk of VTE, MACE and malignancy (see section 4.4) or patients with an inadequate response to 15 mg once daily.
- In adolescents (12 to 17 years of age) weighing at least 30 kg, a dose of 15 mg is recommended.
If the patient does not respond adequately to 15 mg once daily, the dose can be increased to 30 mg once daily.
- The lowest effective dose to maintain response should be used.

For patients 65 years of age and older, the recommended dose is 15 mg once daily (see section 4.4).

Concomitant topical therapies
Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used for sensitive areas such as the face, neck, and intertriginous and genital areas.

Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment.

Alopecia areata

For adults and adolescent patients 12 years of age and older weighing at least 30 kg, the recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.

• A dose of 30 mg once daily may be appropriate for patients with high disease burden or patients with an inadequate response to 15 mg once daily.
• The lowest effective dose to maintain response should be used.

For patients 65 years of age and older, the recommended dose is 15 mg once daily (see section 4.4).

Efficacy data are available for 24 weeks of treatment. The benefit-risk of treatment should be re- assessed at regular intervals on an individual basis.

Vitiligo

The recommended dose of upadacitinib is 15 mg once daily for adults and adolescents 12 years of age and older weighing at least 30 kg.

Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 48 weeks of treatment.

Ulcerative colitis

Induction
The recommended induction dose of upadacitinib is 45 mg once daily for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, upadacitinib 45 mg once daily may be continued for an additional 8-week period (see section 5.1). Upadacitinib should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16.

Maintenance
The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation:
- A dose of 15 mg is recommended for patients at higher risk of VTE, MACE and malignancy (see section 4.4).
- A dose of 30 mg once daily may be appropriate for some patients, such as those with high disease burden or requiring 16-week induction treatment who are not at higher risk of VTE, MACE and malignancy (see section 4.4) or who do not show adequate therapeutic benefit to 15 mg once daily.
- The lowest effective dose to maintain response should be used.

For patients 65 years of age and older, the recommended dose is 15 mg once daily (see section 4.4).

In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Crohn’s disease

Induction
The recommended induction dose of upadacitinib is 45 mg once daily for 12 weeks. For patients who have not achieved adequate therapeutic benefit after the initial 12-week induction, prolonged induction for an additional 12 weeks with a dose of 30 mg once daily may be considered. For these patients, upadacitinib should be discontinued if there is no evidence of therapeutic benefit after 24 weeks of treatment.

Maintenance
The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation:
- A dose of 15 mg is recommended for patients at higher risk of VTE, MACE and malignancy (see section 4.4).
- A dose of 30 mg once daily may be appropriate for patients with high disease burden who are not at higher risk of VTE, MACE and malignancy (see section 4.4) or who do not show adequate therapeutic benefit to 15 mg once daily.
- The lowest effective dose to maintain response should be used.

For patients 65 years of age and older, the recommended maintenance dose is 15 mg once daily (see section 4.4).

In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Interactions

For patients with atopic dermatitis receiving strong inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole, clarithromycin), the recommended dose of upadacitinib is 15 mg once daily. For patients with ulcerative colitis and Crohn’s disease receiving strong CYP3A4 inhibitors, the recommended induction dose is 30 mg once daily and the recommended maintenance dose is 15 mg once daily (see section 4.5).

Dose initiation

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is < 0.5 x 109 cells/L, an absolute neutrophil count (ANC) that is < 1 x 109 cells/L or who have haemoglobin (Hb) levels that are < 8 g/dL (see sections 4.4 and 4.8).

Dose interruption

Treatment should be interrupted if a patient develops a serious infection until the infection is controlled.

Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 2.

Table 2 Laboratory measures and monitoring guidance

Laboratory measure
Action

Monitoring guidance
Absolute
Neutrophil Count
(ANC)
Treatment should be interrupted if ANC is
< 1 x 109 cells/L and may be restarted once
ANC returns above this value
Evaluate at baseline and then no later than 12 weeks after initiation of treatment. Thereafter evaluate according to individual patient management.

Absolute
Lymphocyte
Count (ALC)
Treatment should be interrupted if ALC is
<0.5 x 109 cells/L and may be restarted once ALC returns above this value
Haemoglobin (Hb)
Treatment should be interrupted if Hb is
< 8 g/dL and may be restarted once Hb returns above this value
Hepatic transaminases
Treatment should be temporarily interrupted if drug- induced liver injury is suspected Evaluate at baseline and thereafter according to routine patient management.
Lipids
Patients should be managed according to international clinical guidelines for hyperlipidaemia Evaluate 12 weeks after initiation of treatment and thereafter according to international clinical guidelines for hyperlipidaemia

Special populations

Elderly

Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis
No dose adjustment is required in patients 65 years of age and older. There are limited data in patients 75 years of age and older (see section 4.4).

Atopic dermatitis
For atopic dermatitis, doses higher than 15 mg once daily are not recommended in patients 65 years of age and older (see sections 4.4 and 4.8).

Alopecia areata
The safety and efficacy of upadacitinib in patients 65 years of age and older have not yet been established (see section 4.4).

Vitiligo
There are limited data in patients 65 years of age and older (see sections 4.4 and 4.8).

Ulcerative colitis and Crohn’s disease
For ulcerative colitis and Crohn’s disease, doses higher than 15 mg once daily for maintenance therapy are not recommended in patients 65 years of age and older (see sections 4.4 and 4.8). The safety and efficacy of upadacitinib in patients 75 years of age and older have not yet been established.

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. There are limited data on the use of upadacitinib in subjects with severe renal impairment (see section 5.2). Upadacitinib should be used with caution in patients with severe renal impairment as described in Table 3. The use of upadacitinib has not been studied in subjects with end stage renal disease and is therefore not recommended for use in these patients.

Table 3 Recommended dose for severe renal impairmenta

Therapeutic indication
Recommended once daily dose
Rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, giant cell arteritis, atopic dermatitis, alopecia areata and vitiligo 15 mg Ulcerative colitis, Crohn’s disease Induction: 30 mg Maintenance: 15 mg Polyarticular juvenile idiopathic arthritis No dose adjustment required aestimated glomerular filtration rate (eGFR) 15 to < 30 ml/min/1.73m2

Hepatic impairment

No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment (see section 5.2). Upadacitinib should not be used in patients with severe (Child- Pugh C) hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of RINVOQ in children with polyarticular juvenile idiopathic arthritis weighing < 10 kg or younger than 2 years of age have not been established. No data are available.

The safety and efficacy of RINVOQ in children with atopic dermatitis, alopecia areata or vitiligo below the age of 12 years have not been established. No data are available.

The safety and efficacy of RINVOQ in children and adolescents with psoriatic arthritis, axial spondyloarthritis, ulcerative colitis, or Crohn’s disease, aged 0 to less than 18 years have not yet been established. No data are available.

There is no relevant use of RINVOQ in the paediatric population in the indication giant cell arteritis.

Method of administration

RINVOQ is to be taken orally once daily with or without food and may be taken at any time of the day. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensure the entire dose is delivered correctly.

Treatment with upadacitinib should be initiated and supervised by physicians experienced in the diagnosis and treatment of conditions for which upadacitinib is indicated.

Posology

The recommended dose is based on body weight.

Table 1 Upadacitinib dose for patients with polyarticular juvenile idiopathic arthritis two years of age and older

Patient weight
Dosing regimen
10 to < 20 kg
3 mg (3 ml oral solution) twice daily
20 to < 30 kg
4 mg (4 ml oral solution) twice daily
≥ 30 kg
6 mg (6 ml oral solution) twice daily or
15 mg (one 15 mg tablet) once daily

RINVOQ tablets and RINVOQ oral solution are not bioequivalent. Therefore, the two pharmaceutical forms are not interchangeable on a milligram-per-milligram basis.

Dose initiation

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is < 0.5 x 109 cells/L, an absolute neutrophil count (ANC) that is < 1 x 109 cells/L or who have haemoglobin (Hb) levels that are < 8 g/dL (see sections 4.4 and 4.8).

Dose interruption

Treatment should be interrupted if a patient develops a serious infection until the infection is controlled.

Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 2.

Table 2 Laboratory measures and monitoring guidance

Laboratory measure
Action

Monitoring guidance
Absolute
Neutrophil Count
(ANC)
Treatment should be interrupted if ANC is
< 1 x 109 cells/L and may be restarted once
ANC returns above this value
Evaluate at baseline and then no later than 12 weeks after initiation of treatment. Thereafter evaluate according to individual patient management.

Absolute
Lymphocyte
Count (ALC)
Treatment should be interrupted if ALC is
<0.5 x 109 cells/L and may be restarted once ALC returns above this value
Haemoglobin (Hb)
Treatment should be interrupted if Hb is
< 8 g/dL and may be restarted once Hb returns above this value
Hepatic transaminases
Treatment should be temporarily interrupted if drug- induced liver injury is suspected Evaluate at baseline and thereafter according to routine patient management.
Lipids
Patients should be managed according to international clinical guidelines for hyperlipidaemia Evaluate 12 weeks after initiation of treatment and thereafter according to international clinical guidelines for hyperlipidaemia

Special populations

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. There are limited data on the use of upadacitinib in subjects with severe renal impairment (see section 5.2). Upadacitinib should be used with caution in patients with severe renal impairment. The use of upadacitinib has not been studied in subjects with end stage renal disease and is therefore not recommended for use in these patients.

Hepatic impairment

No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment (see section 5.2). Upadacitinib should not be used in patients with severe (Child- Pugh C) hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of RINVOQ in children weighing < 10 kg or younger than 2 years of age have not been established. No data are available.

Method of administration

RINVOQ oral solution is to be taken orally twice daily with or without food. RINVOQ oral solution should be administered using the provided press-in bottle adapter and oral dosing syringe. After the syringe is attached to the adapter, the bottle is inverted and the correct volume withdrawn. The bottle adapter is placed in the neck of the bottle on first use and should not be removed after it is inserted.

For instructions on preparation and administration of RINVOQ oral solution, refer the patient or caregiver to the Instruction for use (section 7) in the package leaflet.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Active tuberculosis (TB) or active serious infections (see section 4.4).
• Severe hepatic impairment (see section 4.2).
• Pregnancy (see section 4.6).

Summary of the safety profile

In the placebo-controlled clinical trials for rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis, the most commonly reported adverse reactions (≥2% of patients in at least one of the indications with the highest rate among indications presented) with upadacitinib 15 mg were upper respiratory tract infections (19.5%), blood creatine phosphokinase (CPK) increased (8.6%), alanine transaminase increased (4.3%), bronchitis (3.9%), nausea (3.5%), neutropenia (2.8%), cough (2.2%), aspartate transaminase increased (2.2%), and hypercholesterolaemia (2.2%).

In the placebo-controlled atopic dermatitis clinical trials, the most commonly reported adverse reactions (≥2% of patients) with upadacitinib 15 mg or 30 mg were upper respiratory tract infection (25.4%), acne (15.1%), herpes simplex (8.4%), headache (6.3%), blood CPK increased (5.5%), cough (3.2%), folliculitis (3.2%), abdominal pain (2.9%), nausea (2.7%), neutropenia (2.3%), pyrexia (2.1%), and influenza (2.1%).

In the placebo-controlled ulcerative colitis and Crohn’s disease induction and maintenance clinical trials, the most commonly reported adverse reactions (≥3% of patients) with upadacitinib 45 mg, 30 mg or 15 mg were upper respiratory tract infection (19.9%), pyrexia (8.7%), blood CPK increased (7.6%), anaemia (7.4%), headache (6.6%), acne (6.3%), herpes zoster (6.1%), neutropenia (6.0%), rash (5.2%), pneumonia (4.1%), hypercholesterolemia (4.0%), bronchitis (3.9%), aspartate transaminase increased (3.9%), fatigue (3.9%), folliculitis (3.6%), alanine transaminase increased (3.5%), herpes simplex (3.2%), and influenza (3.2%).

The most common serious adverse reactions were serious infections (see section 4.4).

The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications.

Tabulated list of adverse reactions

The following list of adverse reactions is based on clinical studies and post-marketing experience in adults and adolescents. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100);
rare (≥ 1/10 000 to < 1/1 000). The frequencies in Table 4 are based on the higher of the rates for adverse reactions reported with RINVOQ in clinical trials of rheumatologic disease (15 mg tablet), atopic dermatitis (15 mg and 30 mg tablets), alopecia areata (15 mg and 30 mg tablets), vitiligo (15 mg tablet), ulcerative colitis (15 mg, 30 mg and 45 mg tablets), or Crohn’s disease (15 mg, 30 mg, and 45 mg tablets). When notable differences in frequency were observed between indications, these are presented in the footnotes below the table.

Table 4 Adverse reactions

System organ class
Very common
Common
Uncommon
Rare
Infections and infestations
Upper respiratory tract infections
(URTI)a
Bronchitisa,b
Herpes zostera
Herpes simplexa
Folliculitis
Influenza
Urinary tract infection
Pneumoniaa,h
Oral candidiasis
Diverticulitis
Sepsis

Neoplasms benign, malignant and unspecified
(including cysts and polyps)

Non-melanoma skin cancerf

Blood and lymphatic system disorders

Anaemiaa
Neutropeniaa
Lymphopenia

Immune system disorders

Urticariac,g

Serious hypersensitivity reactionsa,e

Metabolism and nutrition disorders

Hypercholesterolaemiaa,b
Hyperlipidaemiaa,b
Hypertriglyceridaemia

Nervous system disorders

Headachea,j
Dizziness

Ear and labyrinth disorders

Vertigoa

Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Abdominal paina
Nausea
Gastrointestinal perforationi

Skin and subcutaneous tissue disorders
Acnea,c,d,g

Rasha

Reproductive system and breast disorders

Semen discolourationl
General disorders and administration site conditions

Fatigue
Pyrexia
Peripheral oedemaa,k

Investigations

Blood CPK increased
ALT increasedb
AST increasedb
Weight increasedg

a Presented as grouped term

b In atopic dermatitis trials, the frequency of bronchitis, hypercholesterolaemia, hyperlipidaemia, ALT increased, and AST increased was uncommon.
c In rheumatologic disease trials, the frequency was common for acne and uncommon for urticaria.
d In ulcerative colitis trials, the frequency was common for acne.
e Serious hypersensitivity reactions including anaphylactic reaction and angioedema f Most events reported as basal cell carcinoma and squamous cell carcinoma of skin g In Crohn’s disease, the frequency was common for acne, and uncommon for urticaria and weight increased.
h Pneumonia was common in Crohn’s disease and uncommon across other indications.
i Frequency is based on Crohn’s disease clinical trials.
j Headache was very common in the giant cell arteritis trial.
k Frequency is based on the giant cell arteritis trial.
l Reports of semen discolouration, mostly blue and less frequently green, have occurred predominantly in patients taking upadacitinib for ulcerative colitis or Crohn’s disease. The clinical significance of semen discolouration is unknown.

Description of selected adverse reactions

Rheumatoid arthritis

Infections

In placebo-controlled clinical studies with background DMARDs, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg group was 27.4% compared to 20.9% in the placebo group. In methotrexate (MTX)-controlled studies, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 19.5% compared to 24.0% in the MTX group. The overall long-term rate of infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies (2 630 patients) was 93.7 events per 100 patient-years.

In placebo-controlled clinical studies with background DMARDs, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg group was 1.2% compared to 0.6% in the placebo group.
In MTX-controlled studies, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 0.6% compared to 0.4% in the MTX group. The overall long-term rate of serious infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.8 events per 100 patient-years. The most common serious infection was pneumonia. The rate of serious infections remained stable with long-term exposure.

Opportunistic infections (excluding tuberculosis)

In placebo-controlled clinical studies with background DMARDs, the frequency of opportunistic infections over 12/14 weeks in the upadacitinib 15 mg group was 0.5% compared to 0.3% in the placebo group. In MTX-controlled studies, there were no cases of opportunistic infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group and 0.2% in the MTX group. The overall long- term rate of opportunistic infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 0.6 events per 100 patient-years.

The long-term rate of herpes zoster for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.7 events per 100 patient-years. Most of the herpes zoster events involved a single dermatome and were non-serious.

Hepatic transaminase elevations

In placebo-controlled studies 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 upadacitinib 15 mg, compared to 1.5% and 0.7%, respectively, of patients treated with placebo. Of the 22 cases of hepatic transaminase elevations, most were asymptomatic and transient.

In MTX-controlled studies, 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 upadacitinib 15 mg, compared to 1.9% and 0.9%, respectively, of patients treated with MTX.

The pattern and incidence of elevation in ALT/AST remained stable over time including in long-term extension studies.

Lipid elevations

Upadacitinib 15 mg treatment was associated with increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 2 to 4 weeks of treatment and remained stable with longer-term treatment. Among patients in the controlled studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 12/14 weeks (including patients who had an isolated elevated value):

• Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 62% vs. 31%, in the upadacitinib 15 mg and placebo groups, respectively
• LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 42% vs. 19%, in the upadacitinib 15 mg and placebo groups, respectively
• HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 89% vs. 61%, in the upadacitinib 15 mg and placebo groups, respectively
• Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 25% vs. 15%, in the upadacitinib 15 mg and placebo groups, respectively

Creatine phosphokinase

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, increases in CPK values were observed. CPK elevations > 5 x upper limit of normal (ULN) were reported in 1.0% and 0.3% of patients over 12/14 weeks in the upadacitinib 15 mg and placebo groups, respectively. Most elevations > 5 x ULN were transient and did not require treatment discontinuation. Mean CPK values increased by 4 weeks with a mean increase of 60 U/L at 12 weeks and then remained stable at an increased value thereafter including with extended therapy.

Neutropenia

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in neutrophil counts below 1 x 109 cells/L in at least one measurement occurred in 1.1% and <0.1% of patients in the upadacitinib 15 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L (see section 4.2). Mean neutrophil counts decreased over 4 to 8 weeks. The decreases in neutrophil counts remained stable at a lower value than baseline over time including with extended therapy.

Psoriatic arthritis

Overall, the safety profile observed in patients with active psoriatic arthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. A higher rate of serious infections (2.6 events per 100 patient-years and 1.3 events per 100 patient-years, respectively) and hepatic transaminase elevations (ALT elevations Grade 3 and higher rates 1.4% and 0.4%, respectively) was observed in patients treated with upadacitinib in combination with MTX therapy compared to patients treated with monotherapy.

Axial spondyloarthritis

Overall, the safety profile observed in patients with active axial spondyloarthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis.

Giant cell arteritis

Overall, the safety profile observed in patients with giant cell arteritis treated with upadacitinib 15 mg was generally consistent with the known safety profile for upadacitinib.

Serious infections

In the placebo-controlled clinical study, the frequency of serious infections over 52 weeks was 5.7% in the upadacitinib 15 mg group and 10.7% in the placebo group. The long-term rate of serious infections was 5.9 events per 100 patient-years for the upadacitinib 15 mg group and 10.5 events per 100 patient- years for the placebo group.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled clinical study, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) over 52 weeks was 1.9% in the upadacitinib 15 mg group and 0.9% in the placebo group. The long-term rate of opportunistic infections (excluding tuberculosis and herpes zoster) was 1.8 events per 100 patient-years for the upadacitinib 15 mg group and 1.5 events per 100 patient-years for the placebo group.

In the placebo-controlled clinical study, the frequency of herpes zoster over 52 weeks was 5.3% in the upadacitinib 15 mg group and 2.7% in the placebo group. The long-term rate of herpes zoster was 5.9 events per 100 patient-years for the upadacitinib 15 mg group and 3.0 events per 100 patient-years for the placebo group.

Atopic dermatitis

Infections

In the placebo-controlled period of the clinical studies, the frequency of infection over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 39% and 43% compared to 30% in the placebo group, respectively. The long-term rate of infections through week 260 for the upadacitinib 15 mg and 30 mg groups was 82.6 and 92.7 events per 100 patient-years, respectively.

In placebo-controlled clinical studies, the frequency of serious infection over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.4% compared to 0.6% in the placebo group, respectively. The long-term rate of serious infections through week 260 for the upadacitinib 15 mg and 30 mg groups was 2.2 and 2.6 events per 100 patient-years, respectively.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled period of the clinical studies, the most frequently reported opportunistic infection (excluding tuberculosis and herpes zoster) was eczema herpeticum. The frequency of eczema herpeticum over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 0.7% and 0.8% compared to 0.4% in the placebo group, respectively. The long-term rate of opportunistic infections (excluding tuberculosis and herpes zoster) through week 260 for the upadacitinib 15 mg and 30 mg groups was 1.7 and 2.0 events per 100 patient-years, respectively. The long-term rate of eczema herpeticum

through week 260 for the upadacitinib 15 mg and 30 mg groups was 1.5 and 1.9 events per 100 patient-years, respectively.

The long-term rate of herpes zoster through week 260 for the upadacitinib 15 mg and 30 mg groups was 3.2 and 5.3 events per 100 patient-years, respectively. Most of the herpes zoster events involved a single dermatome and were non-serious.

Laboratory abnormalities

Dose-dependent changes in ALT increased and/or AST increased (≥ 3 x ULN), lipid parameters, CPK values (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L) associated with upadacitinib treatment were similar to what was observed in the rheumatologic disease clinical studies.

Small increases in LDL cholesterol were observed after week 16 in atopic dermatitis studies. At week 52, the mean increase in LDL cholesterol from baseline was 0.41 mmol/L for upadacitinib 15 mg and 0.56 mmol/L for upadacitinib 30 mg.

Alopecia areata

The safety profile of upadacitinib 15 mg and 30 mg observed in patients with alopecia areata was generally consistent with the known safety profile in patients with atopic dermatitis. No new safety findings were identified.

Vitiligo

The safety profile of upadacitinib 15 mg observed in patients with vitiligo was generally consistent with the known safety profile in patients with atopic dermatitis. No new safety findings were identified. A higher incidence of hypercholesterolaemia was observed in patients with vitiligo treated with upadacitinib 15 mg (3.4%) compared to placebo (2.0%).

Ulcerative colitis

The overall safety profile observed in patients with ulcerative colitis was generally consistent with that observed in patients with rheumatoid arthritis.
A higher rate of herpes zoster was observed with an induction treatment period of 16 weeks vs 8 weeks.

Infections

In the placebo-controlled induction studies, the frequency of infection over 8 weeks in the upadacitinib 45 mg group compared to the placebo group was 20.7% and 17.5%, respectively. In the placebo-controlled maintenance study, the frequency of infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 40.4% and 44.2%, respectively, compared to 38.8% in the placebo group. The long-term rate of infections for upadacitinib 15 mg and 30 mg was 64.5 and 77.8 events per 100 patient-years, respectively.

In the placebo-controlled induction studies, the frequency of serious infection over 8 weeks in both the upadacitinib 45 mg group and the placebo group was 1.3%. No additional serious infections were observed over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.6% and 3.2%, respectively, compared to 3.3% in the placebo group. The long- term rate of serious infections for the upadacitinib 15 mg and 30 mg groups was 3.0 and 4.6 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance phases was COVID-19 pneumonia.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled induction studies over 8 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 45 mg group was 0.4% and 0.3% in the placebo group. No additional opportunistic infections (excluding tuberculosis and herpes zoster) were observed over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study over 52 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.8%, respectively, compared to 0.8% in the placebo group. The long-term rate of opportunistic infections (excluding tuberculosis and herpes zoster) for the upadacitinib 15 mg and 30 mg groups was 0.3 and 0.6 events per 100 patient-years, respectively.

In the placebo-controlled induction studies over 8 weeks, the frequency of herpes zoster in the upadacitinib 45 mg group was 0.6% and 0% in the placebo group. The frequency of herpes zoster was 3.9% over 16-week treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study over 52 weeks, the frequency of herpes zoster in the upadacitinib 15 mg and 30 mg groups was 4.8% and 5.6%, respectively, compared to 0% in the placebo group. The long-term rate of herpes zoster for the upadacitinib 15 mg and 30 mg groups was 4.5 and 7.2 events per 100 patient-years, respectively.

Gastrointestinal perforations

In the placebo-controlled maintenance period, gastrointestinal perforation was reported in 1 patient treated with placebo (1.5 per 100 patient-years) and no patients treated with upadacitinib 15 mg or 30 mg. In the long-term extension study, 1 patient treated with upadacitinib 15 mg (0.1 per 100 patient-years) and 1 patient treated with upadacitinib 30 mg (<0.1 per 100 patient-years) reported events.

Laboratory abnormalities

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L) associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease and atopic dermatitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.

In the placebo-controlled induction studies for up to 8 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 2.0% and 0.8% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 1.6%, 1.2% and 0.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 109 cells/L (see section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.

Elevations in lipid parameters were observed at 8 weeks of treatment with upadacitinib 45 mg and remained generally stable with longer-term treatment with upadacitinib 15 mg and 30 mg. Among patients in the placebo-controlled induction studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 8 weeks (including patients who had an isolated elevated value):

• Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 49% vs. 11%, in the upadacitinib 45 mg and placebo groups, respectively
• LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 27% vs. 9%, in the upadacitinib 45 mg and placebo groups, respectively
• HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 79% vs. 36%, in the upadacitinib 45 mg and placebo groups, respectively
• Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 6% vs 4% in the upadacitinib 45 mg and placebo groups, respectively

Crohn’s disease

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

Serious infections

In the placebo-controlled induction studies, the frequency of serious infection over 12 weeks in the upadacitinib 45 mg group and the placebo group was 1.9% and 1.7%, respectively. In the placebo-controlled maintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.2% and 5.7%, respectively, compared to 4.5% in the placebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups in patients who responded to upadacitinib 45 mg as induction treatment was 5.1 and 7.3 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance studies was gastrointestinal infections.

Gastrointestinal perforations

During the placebo-controlled period in the Phase 3 induction clinical studies, gastrointestinal perforation was reported in 1 patient (0.1%) treated with upadacitinib 45 mg and no patients on placebo through 12 weeks. In all patients treated with upadacitinib 45 mg (n=938) during the induction studies, gastrointestinal perforation was reported in 4 patients (0.4%).

In the long-term placebo-controlled period, gastrointestinal perforation was reported in 1 patient each treated with placebo (0.7 per 100 patient-years), upadacitinib 15 mg (0.4 per 100 patient-years), and upadacitinib 30 mg (0.4 per 100 patient-years). In all patients treated with rescue upadacitinib 30 mg (n=336), gastrointestinal perforation was reported in 3 patients (0.8 per 100 patient-years) through long-term treatment.

Laboratory abnormalities

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), neutropenia (ANC < 1 x 109 cells/L), and lipid parameters associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease, atopic dermatitis and ulcerative colitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.

In the placebo-controlled induction studies for up to 12 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 2.2% and 2.0% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 4.6%, 5.2% and 1.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 109 cells/L (see

section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.

In the placebo-controlled induction studies for up to 12 weeks, decreases in haemoglobin concentration to below 8 g/dL in at least one measurement occurred in 2.7% and 1.4% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in haemoglobin concentration below 8 g/dL in at least one measurement occurred in 1.4%, 4.4% and 2.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to Hb < 8 g/dL (see section 4.2).
No notable mean changes of haemoglobin concentration were observed during upadacitinib treatment over time.

Elderly

Based on the limited data from patients 65 years and older with atopic dermatitis, ulcerative colitis and Crohn’s disease, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose (see section 4.4).

No data was available in patients 65 years of age and older with severe alopecia areata.

Of the 612 patients treated in the vitiligo Phase 3 clinical studies, 55 were 65 years of age or older, of whom 36 were treated with upadacitinib 15 mg during the placebo-controlled period. Overall, the rates of serious and severe adverse reactions in patients 65 years of age or older were comparable between the upadacitinib 15 mg and placebo groups.

Paediatric population

Polyarticular juvenile idiopathic arthritis

A total of 122 paediatric patients (2 to < 18 years of age) with polyarticular juvenile idiopathic arthritis were treated in an open-label, single-arm study, representing 254.6 patient-years of exposure, of whom 113 were exposed to upadacitinib for at least one year. Overall, the safety profile observed in paediatric patients with polyarticular juvenile idiopathic arthritis treated with upadacitinib was consistent with the known safety profile for upadacitinib.

Atopic dermatitis

A total of 541 adolescents aged 12 to 17 years with atopic dermatitis were treated in the global Phase 3 studies (n=343) and the supplemental adolescent substudies (n=198), of whom 264 were exposed to 15 mg and 265 were exposed to 30 mg. The safety profile for upadacitinib 15 mg and 30 mg in adolescents was similar to that in adults through week 260. The long-term rate of the adverse drug reaction of skin papilloma through week 260 for the upadacitinib 15 mg and 30 mg groups was 2.2 and 3.9 events per 100 patient-years, respectively.

Alopecia areata

A total of 117 adolescents aged 12 to 17 years weighing at least 30 kg with alopecia areata were treated with upadacitinib in the placebo-controlled Phase 3 studies, of whom 62 were exposed to 15 mg and 57 were exposed to 30 mg. The safety profile for upadacitinib 15 mg and 30 mg in adolescents was similar to that in adults.

Vitiligo

A total of 52 adolescents with vitiligo aged 12 to 17 years weighing at least 30 kg were treated with upadacitinib 15 mg in the Phase 3 studies, of whom 37 received upadacitinib 15 mg during the placebo-controlled period. The safety profile of upadacitinib 15 mg observed in adolescent patients with vitiligo was generally consistent with the known safety profile in adolescent patients with atopic

dermatitis. No new safety findings were identified. There were no serious adverse events reported in the adolescent population treated with upadacitinib in the placebo-controlled period.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile

In the placebo-controlled clinical trials for rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis, the most commonly reported adverse reactions (≥2% of patients in at least one of the indications with the highest rate among indications presented) with upadacitinib 15 mg were upper respiratory tract infections (19.5%), blood creatine phosphokinase (CPK) increased (8.6%), alanine transaminase increased (4.3%), bronchitis (3.9%), nausea (3.5%), neutropenia (2.8%), cough (2.2%), aspartate transaminase increased (2.2%), and hypercholesterolaemia (2.2%).

In the placebo-controlled atopic dermatitis clinical trials, the most commonly reported adverse reactions (≥2% of patients) with upadacitinib 15 mg or 30 mg were upper respiratory tract infection (25.4%), acne (15.1%), herpes simplex (8.4%), headache (6.3%), blood CPK increased (5.5%), cough (3.2%), folliculitis (3.2%), abdominal pain (2.9%), nausea (2.7%), neutropenia (2.3%), pyrexia (2.1%), and influenza (2.1%).

In the placebo-controlled ulcerative colitis and Crohn’s disease induction and maintenance clinical trials, the most commonly reported adverse reactions (≥3% of patients) with upadacitinib 45 mg, 30 mg or 15 mg were upper respiratory tract infection (19.9%), pyrexia (8.7%), blood CPK increased (7.6%), anaemia (7.4%), headache (6.6%), acne (6.3%), herpes zoster (6.1%), neutropenia (6.0%), rash (5.2%), pneumonia (4.1%), hypercholesterolemia (4.0%), bronchitis (3.9%), aspartate transaminase increased (3.9%), fatigue (3.9%), folliculitis (3.6%), alanine transaminase increased (3.5%), herpes simplex (3.2%), and influenza (3.2%).

The most common serious adverse reactions were serious infections (see section 4.4).

The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications.

Tabulated list of adverse reactions

The following list of adverse reactions is based on clinical studies and post-marketing experience in adults and adolescents with upadacitinib tablets. The frequency of adverse reactions listed below is

defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000). The frequencies in Table 3 are based on the higher of the rates for adverse reactions reported with RINVOQ in clinical trials of rheumatologic disease (15 mg tablet), atopic dermatitis (15 mg and 30 mg tablets), alopecia areata (15 mg and 30 mg tablets), vitiligo (15 mg tablet), ulcerative colitis (15 mg, 30 mg and 45 mg tablets), or Crohn’s disease (15 mg, 30 mg, and 45 mg tablets). When notable differences in frequency were observed between indications, these are presented in the footnotes below the table.

Table 3 Adverse reactions

System organ class
Very common
Common
Uncommon
Rare
Infections and infestations
Upper respiratory tract infections
(URTI)a
Bronchitisa,b
Herpes zostera
Herpes simplexa
Folliculitis
Influenza
Urinary tract infection
Pneumoniaa,h
Oral candidiasis
Diverticulitis
Sepsis

Neoplasms benign, malignant and unspecified
(including cysts and polyps)

Non-melanoma skin cancerf

Blood and lymphatic system disorders

Anaemiaa
Neutropeniaa
Lymphopenia

Immune system disorders

Urticariac,g

Serious hypersensitivity reactionsa,e

Metabolism and nutrition disorders

Hypercholesterolaemiaa,b
Hyperlipidaemiaa,b
Hypertriglyceridaemia

Nervous system disorders

Headachea,j
Dizziness

Ear and labyrinth disorders

Vertigoa

Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Abdominal paina
Nausea
Gastrointestinal perforationi

Skin and subcutaneous tissue disorders
Acnea,c,d,g

Rasha

Reproductive system and breast disorders

Semen discolourationl

General disorders and administration site conditions

Fatigue
Pyrexia
Peripheral oedemaa,k

Investigations

Blood CPK increased
ALT increasedb
AST increasedb
Weight increasedg

a Presented as grouped term b In atopic dermatitis trials, the frequency of bronchitis, hypercholesterolaemia, hyperlipidaemia, ALT increased, and AST increased was uncommon.
c In rheumatologic disease trials, the frequency was common for acne and uncommon for urticaria.
d In ulcerative colitis trials, the frequency was common for acne.
e Serious hypersensitivity reactions including anaphylactic reaction and angioedema f Most events reported as basal cell carcinoma and squamous cell carcinoma of skin g In Crohn’s disease, the frequency was common for acne, and uncommon for urticaria and weight increased.
h Pneumonia was common in Crohn’s disease and uncommon across other indications.
i Frequency is based on Crohn’s disease clinical trials.
j Headache was very common in the giant cell arteritis trial.
k Frequency is based on the giant cell arteritis trial.
l Reports of semen discolouration, mostly blue and less frequently green, have occurred predominantly in patients taking upadacitinib for ulcerative colitis or Crohn’s disease. The clinical significance of semen discolouration is unknown.

Description of selected adverse reactions

Rheumatoid arthritis

Infections

In placebo-controlled clinical studies with background DMARDs, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg group was 27.4% compared to 20.9% in the placebo group. In methotrexate (MTX)-controlled studies, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 19.5% compared to 24.0% in the MTX group. The overall long-term rate of infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies (2 630 patients) was 93.7 events per 100 patient-years.

In placebo-controlled clinical studies with background DMARDs, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg group was 1.2% compared to 0.6% in the placebo group.
In MTX-controlled studies, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 0.6% compared to 0.4% in the MTX group. The overall long-term rate of serious infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.8 events per 100 patient-years. The most common serious infection was pneumonia. The rate of serious infections remained stable with long-term exposure.

Opportunistic infections (excluding tuberculosis)

In placebo-controlled clinical studies with background DMARDs, the frequency of opportunistic infections over 12/14 weeks in the upadacitinib 15 mg group was 0.5% compared to 0.3% in the placebo group. In MTX-controlled studies, there were no cases of opportunistic infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group and 0.2% in the MTX group. The overall long-

term rate of opportunistic infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 0.6 events per 100 patient-years.

The long-term rate of herpes zoster for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.7 events per 100 patient-years. Most of the herpes zoster events involved a single dermatome and were non-serious.

Hepatic transaminase elevations

In placebo-controlled studies 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 upadacitinib 15 mg, compared to 1.5% and 0.7%, respectively, of patients treated with placebo. Of the 22 cases of hepatic transaminase elevations, most were asymptomatic and transient.

In MTX-controlled studies, 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 upadacitinib 15 mg, compared to 1.9% and 0.9%, respectively, of patients treated with MTX.

The pattern and incidence of elevation in ALT/AST remained stable over time including in long-term extension studies.

Lipid elevations

Upadacitinib 15 mg treatment was associated with increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 2 to 4 weeks of treatment and remained stable with longer-term treatment. Among patients in the controlled studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 12/14 weeks (including patients who had an isolated elevated value):

• Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 62% vs. 31%, in the upadacitinib 15 mg and placebo groups, respectively
• LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 42% vs. 19%, in the upadacitinib 15 mg and placebo groups, respectively
• HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 89% vs. 61%, in the upadacitinib 15 mg and placebo groups, respectively
• Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 25% vs. 15%, in the upadacitinib 15 mg and placebo groups, respectively

Creatine phosphokinase

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, increases in CPK values were observed. CPK elevations > 5 x upper limit of normal (ULN) were reported in 1.0% and 0.3% of patients over 12/14 weeks in the upadacitinib 15 mg and placebo groups, respectively. Most elevations > 5 x ULN were transient and did not require treatment discontinuation. Mean CPK values increased by 4 weeks with a mean increase of 60 U/L at 12 weeks and then remained stable at an increased value thereafter including with extended therapy.

Neutropenia

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in neutrophil counts below 1 x 109 cells/L in at least one measurement occurred in 1.1% and <0.1% of patients in the upadacitinib 15 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L (see section 4.2). Mean neutrophil counts decreased

over 4 to 8 weeks. The decreases in neutrophil counts remained stable at a lower value than baseline over time including with extended therapy.

Psoriatic arthritis

Overall, the safety profile observed in patients with active psoriatic arthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. A higher rate of serious infections (2.6 events per 100 patient-years and 1.3 events per 100 patient-years, respectively) and hepatic transaminase elevations (ALT elevations Grade 3 and higher rates 1.4% and 0.4%, respectively) was observed in patients treated with upadacitinib in combination with MTX therapy compared to patients treated with monotherapy.

Axial spondyloarthritis

Overall, the safety profile observed in patients with active axial spondyloarthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis.

Giant cell arteritis

Overall, the safety profile observed in patients with giant cell arteritis treated with upadacitinib 15 mg was generally consistent with the known safety profile for upadacitinib.

Serious infections

In the placebo-controlled clinical study, the frequency of serious infections over 52 weeks was 5.7% in the upadacitinib 15 mg group and 10.7% in the placebo group. The long-term rate of serious infections was 5.9 events per 100 patient-years for the upadacitinib 15 mg group and 10.5 events per 100 patient- years for the placebo group.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled clinical study, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) over 52 weeks was 1.9% in the upadacitinib 15 mg group and 0.9% in the placebo group. The long-term rate of opportunistic infections (excluding tuberculosis and herpes zoster) was 1.8 events per 100 patient-years for the upadacitinib 15 mg group and 1.5 events per 100 patient-years for the placebo group.

In the placebo-controlled clinical study, the frequency of herpes zoster over 52 weeks was 5.3% in the upadacitinib 15 mg group and 2.7% in the placebo group. The long-term rate of herpes zoster was 5.9 events per 100 patient-years for the upadacitinib 15 mg group and 3.0 events per 100 patient-years for the placebo group.

Atopic dermatitis

Infections

In the placebo-controlled period of the clinical studies, the frequency of infection over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 39% and 43% compared to 30% in the placebo group, respectively. The long-term rate of infections through week 260 for the upadacitinib 15 mg and 30 mg groups was 82.6 and 92.7 events per 100 patient-years, respectively.

In placebo-controlled clinical studies, the frequency of serious infection over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.4% compared to 0.6% in the placebo group, respectively. The long-term rate of serious infections through week 260 for the upadacitinib 15 mg and 30 mg groups was 2.2 and 2.6 events per 100 patient-years, respectively.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled period of the clinical studies, the most frequently reported opportunistic infection (excluding tuberculosis and herpes zoster) was eczema herpeticum. The frequency of eczema herpeticum over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 0.7% and 0.8% compared to 0.4% in the placebo group, respectively. The long-term rate of opportunistic infections (excluding tuberculosis and herpes zoster) through week 260 for the upadacitinib 15 mg and 30 mg groups was 1.7 and 2.0 events per 100 patient-years, respectively. The long-term rate of eczema herpeticum through week 260 for the upadacitinib 15 mg and 30 mg groups was 1.5 and 1.9 events per 100 patient-years, respectively.

The long-term rate of herpes zoster through week 260 for the upadacitinib 15 mg and 30 mg groups was 3.2 and 5.3 events per 100 patient-years, respectively. Most of the herpes zoster events involved a single dermatome and were non-serious.

Laboratory abnormalities

Dose-dependent changes in ALT increased and/or AST increased (≥ 3 x ULN), lipid parameters, CPK values (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L) associated with upadacitinib treatment were similar to what was observed in the rheumatologic disease clinical studies.

Small increases in LDL cholesterol were observed after week 16 in atopic dermatitis studies. At week 52, the mean increase in LDL cholesterol from baseline was 0.41 mmol/L for upadacitinib 15 mg and 0.56 mmol/L for upadacitinib 30 mg.

Alopecia areata

The safety profile of upadacitinib 15 mg and 30 mg observed in patients with alopecia areata was generally consistent with the known safety profile in patients with atopic dermatitis. No new safety findings were identified.

Vitiligo

The safety profile of upadacitinib 15 mg observed in patients with vitiligo was generally consistent with the known safety profile in patients with atopic dermatitis. No new safety findings were identified. A higher incidence of hypercholesterolaemia was observed in patients with vitiligo treated with upadacitinib 15 mg (3.4%) compared to placebo (2.0%).

Ulcerative colitis

The overall safety profile observed in patients with ulcerative colitis was generally consistent with that observed in patients with rheumatoid arthritis.
A higher rate of herpes zoster was observed with an induction treatment period of 16 weeks vs 8 weeks.

Infections

In the placebo-controlled induction studies, the frequency of infection over 8 weeks in the upadacitinib 45 mg group compared to the placebo group was 20.7% and 17.5%, respectively. In the placebo-controlled maintenance study, the frequency of infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 40.4% and 44.2%, respectively, compared to 38.8% in the placebo group. The long-term rate of infections for upadacitinib 15 mg and 30 mg was 64.5 and 77.8 events per 100 patient-years, respectively.

In the placebo-controlled induction studies, the frequency of serious infection over 8 weeks in both the upadacitinib 45 mg group and the placebo group was 1.3%. No additional serious infections were observed over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlled

maintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.6% and 3.2%, respectively, compared to 3.3% in the placebo group. The long- term rate of serious infections for the upadacitinib 15 mg and 30 mg groups was 3.0 and 4.6 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance phases was COVID-19 pneumonia.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled induction studies over 8 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 45 mg group was 0.4% and 0.3% in the placebo group. No additional opportunistic infections (excluding tuberculosis and herpes zoster) were observed over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study over 52 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.8%, respectively, compared to 0.8% in the placebo group. The long-term rate of opportunistic infections (excluding tuberculosis and herpes zoster) for the upadacitinib 15 mg and 30 mg groups was 0.3 and 0.6 events per 100 patient-years, respectively.

In the placebo-controlled induction studies over 8 weeks, the frequency of herpes zoster in the upadacitinib 45 mg group was 0.6% and 0% in the placebo group. The frequency of herpes zoster was 3.9% over 16-week treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study over 52 weeks, the frequency of herpes zoster in the upadacitinib 15 mg and 30 mg groups was 4.8% and 5.6%, respectively, compared to 0% in the placebo group. The long-term rate of herpes zoster for the upadacitinib 15 mg and 30 mg groups was 4.5 and 7.2 events per 100 patient-years, respectively.

Gastrointestinal perforations

In the placebo-controlled maintenance period, gastrointestinal perforation was reported in 1 patient treated with placebo (1.5 per 100 patient-years) and no patients treated with upadacitinib 15 mg or 30 mg. In the long-term extension study, 1 patient treated with upadacitinib 15 mg (0.1 per 100 patient-years) and 1 patient treated with upadacitinib 30 mg (<0.1 per 100 patient-years) reported events.

Laboratory abnormalities

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L) associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease and atopic dermatitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.

In the placebo-controlled induction studies for up to 8 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 2.0% and 0.8% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 1.6%, 1.2% and 0.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 109 cells/L (see section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.

Elevations in lipid parameters were observed at 8 weeks of treatment with upadacitinib 45 mg and remained generally stable with longer-term treatment with upadacitinib 15 mg and 30 mg. Among patients in the placebo-controlled induction studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 8 weeks (including patients who had an isolated elevated value):

• Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 49% vs. 11%, in the upadacitinib 45 mg and placebo groups, respectively
• LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 27% vs. 9%, in the upadacitinib 45 mg and placebo groups, respectively
• HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 79% vs. 36%, in the upadacitinib 45 mg and placebo groups, respectively
• Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 6% vs 4% in the upadacitinib 45 mg and placebo groups, respectively

Crohn’s disease

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

Serious infections

In the placebo-controlled induction studies, the frequency of serious infection over 12 weeks in the upadacitinib 45 mg group and the placebo group was 1.9% and 1.7%, respectively. In the placebo-controlled maintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.2% and 5.7%, respectively, compared to 4.5% in the placebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups in patients who responded to upadacitinib 45 mg as induction treatment was 5.1 and 7.3 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance studies was gastrointestinal infections.

Gastrointestinal perforations

During the placebo-controlled period in the Phase 3 induction clinical studies, gastrointestinal perforation was reported in 1 patient (0.1%) treated with upadacitinib 45 mg and no patients on placebo through 12 weeks. In all patients treated with upadacitinib 45 mg (n=938) during the induction studies, gastrointestinal perforation was reported in 4 patients (0.4%).

In the long-term placebo-controlled period, gastrointestinal perforation was reported in 1 patient each treated with placebo (0.7 per 100 patient-years), upadacitinib 15 mg (0.4 per 100 patient-years), and upadacitinib 30 mg (0.4 per 100 patient-years). In all patients treated with rescue upadacitinib 30 mg (n=336), gastrointestinal perforation was reported in 3 patients (0.8 per 100 patient-years) through long-term treatment.

Laboratory abnormalities

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), neutropenia (ANC < 1 x 109 cells/L), and lipid parameters associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease, atopic dermatitis and ulcerative colitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.

In the placebo-controlled induction studies for up to 12 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 2.2% and 2.0% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurred in 4.6%, 5.2% and 1.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 109 cells/L (see

section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.

In the placebo-controlled induction studies for up to 12 weeks, decreases in haemoglobin concentration to below 8 g/dL in at least one measurement occurred in 2.7% and 1.4% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in haemoglobin concentration below 8 g/dL in at least one measurement occurred in 1.4%, 4.4% and 2.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to Hb < 8 g/dL (see section 4.2).
No notable mean changes of haemoglobin concentration were observed during upadacitinib treatment over time.

Elderly

Based on the limited data from patients 65 years and older with atopic dermatitis, ulcerative colitis and Crohn’s disease, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose (see section 4.4).

No data was available in patients 65 years of age and older with severe alopecia areata.

Of the 612 patients treated in the vitiligo Phase 3 clinical studies, 55 were 65 years of age or older, of whom 36 were treated with upadacitinib 15 mg during the placebo-controlled period. Overall, the rates of serious and severe adverse reactions in patients 65 years of age or older were comparable between the upadacitinib 15 mg and placebo groups.

Paediatric population

Polyarticular juvenile idiopathic arthritis

A total of 122 paediatric patients (2 to < 18 years of age) with polyarticular juvenile idiopathic arthritis were treated in an open-label, single-arm study, representing 254.6 patient-years of exposure, of whom 113 were exposed to upadacitinib for at least one year. Overall, the safety profile observed in paediatric patients with polyarticular juvenile idiopathic arthritis treated with upadacitinib was consistent with the known safety profile for upadacitinib.

Atopic dermatitis

A total of 541 adolescents aged 12 to 17 years with atopic dermatitis were treated in the global Phase 3 studies (n=343) and the supplemental adolescent substudies (n=198), of whom 264 were exposed to 15 mg and 265 were exposed to 30 mg. The safety profile for upadacitinib 15 mg and 30 mg in adolescents was similar to that in adults through week 260. The long-term rate of the adverse drug reaction of skin papilloma through week 260 for the upadacitinib 15 mg and 30 mg groups was 2.2 and 3.9 events per 100 patient-years, respectively.

Alopecia areata

A total of 117 adolescents aged 12 to 17 years weighing at least 30 kg with alopecia areata were treated with upadacitinib in the placebo-controlled Phase 3 studies, of whom 62 were exposed to 15 mg and 57 were exposed to 30 mg. The safety profile for upadacitinib 15 mg and 30 mg in adolescents was similar to that in adults.

Vitiligo

A total of 52 adolescents with vitiligo aged 12 to 17 years weighing at least 30 kg were treated with upadacitinib 15 mg in the Phase 3 studies, of whom 37 received upadacitinib 15 mg during the placebo-controlled period. The safety profile of upadacitinib 15 mg observed in adolescent patients with vitiligo was generally consistent with the known safety profile in adolescent patients with atopic

dermatitis. No new safety findings were identified. There were no serious adverse events reported in the adolescent population treated with upadacitinib in the placebo-controlled period.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Upadacitinib should only be used if no suitable treatment alternatives are available in patients:
- 65 years of age and older;
- patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers);
- patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Use in patients 65 years of age and older

Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients 65 years of age and older, as observed in a large randomised study of tofacitinib (another Janus Kinase (JAK) inhibitor), upadacitinib should only be used in these patients if no suitable treatment alternatives are available.

In patients 65 years of age and older, there is an increased risk of adverse reactions with upadacitinib 30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is 15 mg once daily (see sections 4.2 and 4.8).

Immunosuppressive medicinal products

Combination with other potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.

Serious infections

Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported with upadacitinib included pneumonia (see section 4.8) and cellulitis. Cases of bacterial meningitis and sepsis have been reported in patients receiving upadacitinib. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis were reported with upadacitinib.

Upadacitinib should not be initiated in patients with an active, serious infection, including localised infections (see section 4.3).

Consider the risks and benefits of treatment prior to initiating upadacitinib 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 travelled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Upadacitinib therapy should be interrupted 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 therapy should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib therapy may be resumed once the infection is controlled.

A higher rate of serious infections was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.

As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients 65 years of age and older, upadacitinib should only be used if no suitable treatment alternatives are available (see section 4.2).

Tuberculosis

Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinib should not be given to patients with active TB (see section 4.3). Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with 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.

Patients should be monitored 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), was reported in clinical studies (see section 4.8). The risk of herpes zoster appears to be higher in Japanese patients treated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.

Vaccination

No data are available on the response to vaccination with live vaccines in patients receiving upadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended. Prior to initiating upadacitinib treatment, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines (see section 5.1).

Malignancy

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.

A higher rate of malignancies was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.

In patients 65 years of age and older, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g., current malignancy or history of malignancy), upadacitinib should only be used if no suitable treatment alternatives are available.

Non-melanoma skin cancer (NMSC)

NMSCs have been reported in patients treated with upadacitinib (see section 4.8). A higher rate of NMSC was observed with upadacitinib 30 mg compared to upadacitinib 15 mg. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Haematological abnormalities

Absolute Neutrophil Count (ANC) < 1 x 109 cells/L, Absolute Lymphocyte Count (ALC) < 0.5 x 109 cells/L and haemoglobin < 8 g/dL were reported in ≤1 % of patients in clinical trials (see section 4.8).
Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 x 109 cells/L, ALC < 0.5 x 109 cells/L or haemoglobin < 8 g/dL observed during routine patient management (see section 4.2).

Gastrointestinal perforations

Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and from post-marketing sources (see section 4.8).

Upadacitinib should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or opioids). Patients with active Crohn’s disease are at increased risk for developing intestinal perforation. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.

Major adverse cardiovascular events

Events of MACE were observed in clinical studies of upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors.

Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, upadacitinib should only be used if no suitable treatment alternatives are available.

Lipids

Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see section 4.8). Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations

on cardiovascular morbidity and mortality has not been determined (see section 4.2 for monitoring guidance).

Hepatic transaminase elevations

Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo (see section 4.8).

Hepatic transaminases must be evaluated 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 therapy should be interrupted until this diagnosis is excluded.

Venous thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in clinical trials for upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose-dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to TNF inhibitors.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adverse cardiovascular events” and “Malignancy”) upadacitinib should only be used if no suitable treatment alternatives are available.

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, upadacitinib should be used with caution. VTE risk factors other than cardiovascular or malignancy risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder. Patients should be re-evaluated periodically during upadacitinib treatment to assess for changes in VTE risk. Patients with signs and symptoms of VTE should be promptly evaluated and treatment should be discontinued in patients with suspected VTE, regardless of dose.

Retinal vein occlusion

Retinal vein occlusion has been reported in patients treated with JAK inhibitors, including upadacitinib.
Patients should be advised to promptly seek medical care in case they experience symptoms suggestive of retinal vein occlusion.

Hypersensitivity reactions

Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients receiving upadacitinib. If a clinically significant hypersensitivity reaction occurs, treatment with upadacitinib must be discontinued and appropriate therapy must be instituted (see sections 4.3 and 4.8).

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of JAK inhibitors, including upadacitinib, in patients receiving treatment for diabetes. Dose adjustment of anti-diabetic medicinal products may be necessary in the event that hypoglycaemia occurs.

Medication residue in stool

Reports of medication residue in stool or ostomy output have occurred in patients taking upadacitinib.
Most reports described anatomic (e.g., ileostomy, colostomy, intestinal resection) or functional gastrointestinal conditions with shortened gastrointestinal transit times. Patients should be instructed to contact their healthcare professional if medication residue is observed repeatedly. Patients should be clinically monitored, and alternative treatment should be considered if there is an inadequate therapeutic response.

Giant cell arteritis

Upadacitinib monotherapy should not be used for the treatment of acute relapses as efficacy in this setting has not been established. Corticosteroids should be given according to medical judgement and practice guidelines.

Upadacitinib should only be used if no suitable treatment alternatives are available in patients:
- 65 years of age and older;
- patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers);
- patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Use in patients 65 years of age and older

Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients 65 years of age and older, as observed in a large randomised study of tofacitinib (another Janus Kinase (JAK) inhibitor), upadacitinib should only be used in these patients if no suitable treatment alternatives are available.

In patients 65 years of age and older, there is an increased risk of adverse reactions with upadacitinib 30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is 15 mg once daily (see sections 4.2 and 4.8).

Immunosuppressive medicinal products

Combination with other potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.

Serious infections

Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported with upadacitinib included pneumonia (see section 4.8) and cellulitis. Cases of bacterial meningitis and sepsis have been reported in patients receiving upadacitinib. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis were reported with upadacitinib.

Upadacitinib should not be initiated in patients with an active, serious infection, including localised infections (see section 4.3).

Consider the risks and benefits of treatment prior to initiating upadacitinib 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 travelled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Upadacitinib therapy should be interrupted 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 therapy should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib therapy may be resumed once the infection is controlled.

A higher rate of serious infections was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.

As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients 65 years of age and older, upadacitinib should only be used if no suitable treatment alternatives are available (see section 4.2).

Tuberculosis

Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinib should not be given to patients with active TB (see section 4.3). Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with 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.

Patients should be monitored 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), was reported in clinical studies (see section 4.8). The risk of herpes zoster appears to be higher in Japanese patients treated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.

Vaccination

No data are available on the response to vaccination with live vaccines in patients receiving upadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended. Prior to initiating upadacitinib treatment, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines (see section 5.1).

Malignancy

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.

A higher rate of malignancies was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.

In patients 65 years of age and older, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g., current malignancy or history of malignancy), upadacitinib should only be used if no suitable treatment alternatives are available.

Non-melanoma skin cancer (NMSC)

NMSCs have been reported in patients treated with upadacitinib (see section 4.8). A higher rate of NMSC was observed with upadacitinib 30 mg compared to upadacitinib 15 mg. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Haematological abnormalities

Absolute Neutrophil Count (ANC) < 1 x 109 cells/L, Absolute Lymphocyte Count (ALC) < 0.5 x 109 cells/L and haemoglobin < 8 g/dL were reported in ≤1 % of patients in clinical trials (see section 4.8).
Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 x 109 cells/L, ALC < 0.5 x 109 cells/L or haemoglobin < 8 g/dL observed during routine patient management (see section 4.2).

Gastrointestinal perforations

Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and from post-marketing sources (see section 4.8).

Upadacitinib should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or opioids). Patients with active Crohn’s disease are at increased risk for developing intestinal perforation. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.

Major adverse cardiovascular events

Events of MACE were observed in clinical studies of upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors.

Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, upadacitinib should only be used if no suitable treatment alternatives are available.

Lipids

Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see section 4.8). Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined (see section 4.2 for monitoring guidance).

Hepatic transaminase elevations

Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo (see section 4.8).

Hepatic transaminases must be evaluated 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 therapy should be interrupted until this diagnosis is excluded.

Venous thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in clinical trials for upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose-dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to TNF inhibitors.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adverse cardiovascular events” and “Malignancy”) upadacitinib should only be used if no suitable treatment alternatives are available.

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, upadacitinib should be used with caution. VTE risk factors other than cardiovascular or malignancy risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder. Patients should be re-evaluated periodically during upadacitinib treatment to assess for changes in VTE risk. Patients with signs and symptoms of VTE should be promptly evaluated and treatment should be discontinued in patients with suspected VTE, regardless of dose.

Retinal vein occlusion

Retinal vein occlusion has been reported in patients treated with JAK inhibitors, including upadacitinib.
Patients should be advised to promptly seek medical care in case they experience symptoms suggestive of retinal vein occlusion.

Hypersensitivity reactions

Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients receiving upadacitinib. If a clinically significant hypersensitivity reaction occurs, treatment with upadacitinib must be discontinued and appropriate therapy must be instituted (see sections 4.3 and 4.8).

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of JAK inhibitors, including upadacitinib, in patients receiving treatment for diabetes. Dose adjustment of anti-diabetic medicinal products may be necessary in the event that hypoglycaemia occurs.

Excipients with known effect

Sodium benzoate
This medicinal product contains 0.3 mg sodium benzoate in each ml.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-free’.

Potential for other medicinal products to affect the pharmacokinetics of upadacitinib

Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can be affected by medicinal products that strongly inhibit or induce CYP3A4.

Co-administration with CYP3A4 inhibitors

Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, and grapefruit). In a clinical study, co-administration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib Cmax and AUC, respectively. Upadacitinib 15 mg tablets once daily or 3 mg, 4 mg, or 6 mg of the oral solution twice daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. For patients with atopic dermatitis or alopecia areata using strong CYP3A4 inhibitors, the recommended dose of upadacitinib is 15 mg once daily. For patients with ulcerative colitis or Crohn’s disease using strong CYP3A4 inhibitors, the recommended induction dose is 30 mg once daily and the recommended maintenance dose is 15 mg once daily (see section 4.2). Alternatives to strong CYP3A4 inhibitors should be considered when used in the long-term. Food or drink containing grapefruit should be avoided during treatment with upadacitinib.

Co-administration with CYP3A4 inducers

Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinical study, co-administration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer) resulted in approximately 50% and 60% decreases in upadacitinib Cmax and AUC, respectively.
Patients should be monitored for changes in disease activity if upadacitinib is co-administered with strong CYP3A4 inducers.

Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures.

Potential for upadacitinib to affect the pharmacokinetics of other medicinal products

Administration of multiple 30 mg or 45 mg once daily doses of upadacitinib to healthy subjects had a limited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (24-26% decrease in midazolam AUC and Cmax), indicating that upadacitinib 30 mg or 45 mg once daily may have a weak induction effect on CYP3A. In a clinical study, rosuvastatin and atorvastatin AUC were decreased by 33% and 23%, respectively, and rosuvastatin Cmax was decreased by 23% following the administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevant effect on atorvastatin Cmax or on plasma exposures of ortho-hydroxyatorvastatin (major active

metabolite for atorvastatin). Administration of multiple 45 mg once daily doses of upadacitinib to healthy subjects led to a limited increase in AUC and Cmax of dextromethorphan (sensitive CYP2D6 substrate) by 30% and 35%, respectively, indicating that upadacitinib 45 mg once daily has a weak inhibitory effect on CYP2D6. No dose adjustment is recommended for CYP3A substrates, CYP2D6 substrates, rosuvastatin or atorvastatin when co-administered with upadacitinib.

Upadacitinib has no relevant effects on plasma exposures of ethinyl estradiol, levonorgestrel, methotrexate, or medicinal products that are substrates for metabolism by CYP1A2, CYP2B6, CYP2C9, or CYP2C19.

Potential for other medicinal products to affect the pharmacokinetics of upadacitinib

Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can be affected by medicinal products that strongly inhibit or induce CYP3A4.

Co-administration with CYP3A4 inhibitors

Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, and grapefruit). In a clinical study, co-administration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib Cmax and AUC, respectively. Upadacitinib 15 mg tablets once daily or 3 mg, 4 mg, or 6 mg of the oral solution twice daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Alternatives to strong CYP3A4 inhibitors should be considered when used in the long-term. Food or drink containing grapefruit should be avoided during treatment with upadacitinib.

Co-administration with CYP3A4 inducers

Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinical study, co-administration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer) resulted in approximately 50% and 60% decreases in upadacitinib Cmax and AUC, respectively.
Patients should be monitored for changes in disease activity if upadacitinib is co-administered with strong CYP3A4 inducers.

Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures.

Potential for upadacitinib to affect the pharmacokinetics of other medicinal products

Administration of multiple 30 mg or 45 mg once daily doses of upadacitinib tablets to healthy subjects had a limited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (24-26% decrease in midazolam AUC and Cmax), indicating that upadacitinib 30 mg or 45 mg tablet once daily may have a weak induction effect on CYP3A. In a clinical study, rosuvastatin and atorvastatin AUC were decreased by 33% and 23%, respectively, and rosuvastatin Cmax was decreased by 23% following the administration of multiple 30 mg tablet once daily doses of upadacitinib to healthy subjects.
Upadacitinib had no relevant effect on atorvastatin Cmax or on plasma exposures of ortho- hydroxyatorvastatin (major active metabolite for atorvastatin). Administration of multiple 45 mg tablet once daily doses of upadacitinib to healthy subjects led to a limited increase in AUC and Cmax of dextromethorphan (sensitive CYP2D6 substrate) by 30% and 35%, respectively, indicating that upadacitinib 45 mg tablet once daily has a weak inhibitory effect on CYP2D6. No dose adjustment is recommended for CYP3A substrates, CYP2D6 substrates, rosuvastatin or atorvastatin when co- administered with upadacitinib.

Upadacitinib has no relevant effects on plasma exposures of ethinyl estradiol, levonorgestrel, methotrexate, or medicinal products that are substrates for metabolism by CYP1A2, CYP2B6, CYP2C9, or CYP2C19.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and for 4 weeks following the final dose of upadacitinib. Female paediatric patients and/or their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib.

Pregnancy

There are no or limited data on the use of upadacitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Upadacitinib was teratogenic in rats and rabbits with effects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero.

Upadacitinib is contraindicated during pregnancy (see section 4.3).

If a patient becomes pregnant while taking upadacitinib the parents should be informed of the potential risk to the foetus.

Breast-feeding

It is unknown whether upadacitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see section 5.3).

A risk to newborns/infants cannot be excluded.

Upadacitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue upadacitinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of upadacitinib on human fertility has not been evaluated. Animal studies do not indicate effects with respect to fertility (see section 5.3).

Upadacitinib may have a minor influence on the ability to drive and use machines because dizziness and vertigo may occur during treatment with RINVOQ (see section 4.8).

Upadacitinib was administered in clinical studies up to doses equivalent in daily AUC to 60 mg prolonged-release once daily. Adverse reactions were comparable to those seen at lower doses and no specific toxicities were identified. Approximately 90% of upadacitinib in the systemic circulation is eliminated within 24 hours of dosing (within the range of doses evaluated in clinical studies). In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, Janus-associated kinase (JAK) inhibitors ATC code: L04AF03

Mechanism of action

Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit cytokine or growth factor signals involved in a broad range of cellular processes including inflammatory responses, hematopoiesis, and immune surveillance. The JAK family of enzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylate and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function.

In human cellular assays, upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Atopic dermatitis is driven by pro-inflammatory cytokines (including IL-4, IL-13, IL-22, TSLP, IL-31 and IFN-γ) that transduce signals via the JAK1 pathway. Inhibiting JAK1 with upadacitinib reduces the signalling of many mediators which drive the signs and symptoms of atopic dermatitis such as eczematous skin lesions and pruritus. Pro-inflammatory cytokines that transduce signals via the JAK1 pathway are involved in the pathology of alopecia areata, although the complete pathophysiology is still not understood.
Inhibition of JAK1 by upadacitinib modulates JAK-mediated inflammation, which allows hair regrowth in patients with alopecia areata. Proinflammatory cytokines that transduce signals via the JAK1 pathway are involved in the pathogenesis of vitiligo, although the complete pathophysiology is still not fully understood. Inhibition of JAK1 by upadacitinib blocks the signalling of the JAK- dependent cytokines and chemokines (e.g., IFNγ, IL-15, IL-7, CXCL9, CXCL10) to restore normal melanocyte function, and thereby allows stabilisation of disease and enables repigmentation.
Pro-inflammatory cytokines (primarily IL-6, IL-7, IL-15 and IFNγ) transduce signals via the JAK1 pathway and are involved in the pathology of inflammatory bowel diseases. JAK1 inhibition with upadacitinib modulates the signalling of the JAK-dependent cytokines underlying the inflammatory burden and signs and symptoms of inflammatory bowel diseases.

Pharmacodynamic effects

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

Pharmacotherapeutic group: Immunosuppressants, Janus-associated kinase (JAK) inhibitors, ATC code: L04AF03

Mechanism of action

Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit cytokine or growth factor signals involved in a broad range of cellular processes including inflammatory responses, hematopoiesis, and immune surveillance. The JAK family of enzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylate and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function.

In human cellular assays, upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2.

Pharmacodynamic effects

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.

hsCRP

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with decreases from baseline in mean hsCRP levels as early as week 1 which were maintained with continued treatment.

Vaccine studies

The influence of upadacitinib on the humoral response following administration of adjuvanted recombinant glycoprotein E herpes zoster vaccine was evaluated in 93 patients with rheumatoid arthritis under stable treatment with upadacitinib 15 mg. 98% of patients were on concomitant methotrexate. 49% of patients were on oral corticosteroids at baseline. The primary endpoint was the proportion of patients with a satisfactory humoral response defined as ≥ 4-fold increase in pre- vaccination concentration of anti-glycoprotein E titer levels at week 16 (4 weeks post-dose 2 vaccination). Vaccination of patients treated with upadacitinib 15 mg resulted in a satisfactory humoral response in 79/90 (88% [95% CI: 81.0, 94.5]) of patients at week 16.

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after multiple once daily administrations of the tablet.

RINVOQ tablets and RINVOQ oral solution are not bioequivalent. Therefore, the two pharmaceutical forms are not interchangeable on a milligram-per-milligram basis (see section 4.2).

Absorption

Following oral administration of upadacitinib prolonged-release formulation, upadacitinib is absorbed with a median Tmax of 2 to 4 hours. Coadministration of upadacitinib with a high-fat meal had no clinically relevant effect on upadacitinib exposures (increased AUC by 29% and Cmax by 39% to 60%).
In clinical trials, upadacitinib was administered without regard to meals (see section 4.2). In vitro, upadacitinib is a substrate for the efflux transporters P-gp and BCRP.

Distribution

Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components, as indicated by the blood to plasma ratio of 1.0.

Biotransformation

Upadacitinib metabolism is mediated 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 (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.

Elimination

Following single dose administration of [14C]-upadacitinib immediate-release solution, upadacitinib was eliminated predominantly as the unchanged parent substance in urine (24%) and faeces (38%).
Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminal elimination half-life ranged from 9 to 14 hours.

Special populations

Renal impairment

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after multiple once daily administrations of the tablet.

RINVOQ tablets and RINVOQ oral solution are not bioequivalent. Therefore, the two pharmaceutical forms are not interchangeable on a milligram-per-milligram basis (see section 4.2).

Absorption

Following oral administration of 6 mg upadacitinib oral solution, upadacitinib is absorbed with a median Tmax of 1 hour. Coadministration of upadacitinib oral solution with food is not expected to have a clinically relevant effect on upadacitinib exposure. In clinical trials, upadacitinib was administered without regard to meals (see section 4.2). In vitro, upadacitinib is a substrate for the efflux transporters P-gp and BCRP.

Distribution

Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components, as indicated by the blood to plasma ratio of 1.0.

Biotransformation

Upadacitinib metabolism is mediated 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 (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.

Elimination

Following single dose administration of [14C]-upadacitinib immediate-release solution, upadacitinib was eliminated predominantly as the unchanged parent substance in urine (24%) and faeces (38%).
Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminal elimination half-life is 6 hours.

Special populations

Renal impairment