ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS

1This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
RINVOQ 30 mg prolonged-release tablets
RINVOQ 45 mg prolonged-release tablets
2.

QUALITATIVE AND QUANTITATIVE COMPOSITIONRINVOQ 15 mg prolonged-release tablets
Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg of upadacitinib.
RINVOQ 30 mg prolonged-release tablets
Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg of upadacitinib.
RINVOQ 45 mg prolonged-release tablets
Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 45 mg of upadacitinib.
For the full list of excipients, see section 6.1.
3.

PHARMACEUTICAL FORM

Prolonged-release tablet
RINVOQ 15 mg prolonged-release tablets
Purple 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one side with ‘a15’.
RINVOQ 30 mg prolonged-release tablets
Red 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one side with ‘a30’.
RINVOQ 45 mg prolonged-release tablets
Yellow to mottled yellow 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one sidewith ‘a45’.
4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Rheumatoid arthritis
RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis in adultpatients 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 withmethotrexate.
2

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.
Axial spondyloarthritis
Non-radiographic axial spondyloarthritis (nr-axSpA)
RINVOQ is indicated for the treatment of active non-radiographic axial spondyloarthritis in adultpatients 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 antiinflammatory 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.
Atopic dermatitis
RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults andadolescents 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’sdisease who have had an inadequate response, lost response or were intolerant to either conventional
therapy or a biologic agent.
4.2

Posology and method of administration

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.

3Atopic dermatitis
Adults
The recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patientpresentation.
•••

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 aninadequate 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).
Adolescents (from 12 to 17 years of age)
The recommended dose of upadacitinib is 15 mg once daily for adolescents weighing at least 30 kg.
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 noevidence of therapeutic benefit after 12 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 becontinued for an additional 8 weeks (see sections 4.8 and 5.1). Upadacitinib should be discontinued inany 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 highdisease 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,
4

upadacitinib should be discontinued if there is no evidence of therapeutic benefit after 24 weeks oftreatment.
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 showadequate 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 (seesection 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 ulcerative colitis and Crohn’s disease receiving strong inhibitors of cytochrome P450
(CYP) 3A4 (e.g., ketoconazole, clarithromycin), 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 iscontrolled.
Interruption of dosing may be needed for management of laboratory abnormalities as described inTable 1.
Table 1 Laboratory measures and monitoring guidance
Laboratory
measureAbsolute
Neutrophil Count(ANC)

Absolute
Lymphocyte
Count (ALC)

ActionMonitoring guidance

Treatment should beinterrupted if ANC is< 1 x 109 cells/L andmay be restarted once
ANC returns above
this value
Treatment should beinterrupted if ALC is<0.5 x 109 cells/Land may be restarted
once ALC 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.

5

Haemoglobin (Hb)

Hepatictransaminases

LipidsTreatment should beinterrupted if Hb is< 8 g/dL and may berestarted once Hbreturns above thisvalue
Treatment should be
temporarily
interrupted if druginduced liver injury
is suspected
Patients should bemanaged according
to international
clinical guidelines for
hyperlipidaemia

Evaluate at baseline and thereafter according toroutine patient management.

Evaluate 12 weeks after initiation of treatment andthereafter according to international clinicalguidelines for hyperlipidaemia

Special populations
Elderly
Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis
There are limited data in patients 75 years of age and older.
Atopic dermatitis
For atopic dermatitis, doses higher than 15 mg once daily are not recommended in patients 65 years ofage and older (see section 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 section 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 2. The useof upadacitinib has not been studied in subjects with end stage renal disease and is therefore notrecommended for use in these patients.
Table 2 Recommended dose for severe renal impairmenta
Therapeutic indication

Recommended once daily dose

Rheumatoid arthritis, psoriatic arthritis,
axial spondyloarthritis, atopic dermatitis

15 mg

Ulcerative colitis, Crohn’s disease

Induction: 30 mg
Maintenance: 15 mgaestimated glomerular filtration rate (eGFR) 15 to < 30 ml/min/1.73m2

6

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 (ChildPugh C) hepatic impairment (see section 4.3).
Paediatric population
The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years havenot been established. No data are available. No clinical exposure data are available in adolescents< 40 kg (see section 5.2).
The safety and efficacy of RINVOQ in children and adolescents with rheumatoid arthritis, psoriatic
arthritis, axial spondyloarthritis, ulcerative colitis, and Crohn’s disease, aged 0 to less than 18 years
have not yet been established. No data are available.
Method of administration
RINVOQ is to be taken orally once daily with or without food and may be taken at any time of theday. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensure
the entire dose is delivered correctly.
4.3

Contraindications

•
•
•
•

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).

4.4

Special warnings and precautions for use

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 inpatients 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 inclinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.

7

Serious infections
Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The mostfrequent serious infections reported with upadacitinib included pneumonia and cellulitis (seesection 4.8). 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.
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; orwith 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 withupadacitinib 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 toantimicrobial 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 (seesection 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 thedecision 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 inclinical studies (see section 4.8). The risk of herpes zoster appears to be higher in Japanese patientstreated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapy
should be considered until the episode resolves.

8Screening for viral hepatitis and monitoring for reactivation should be performed before starting andduring 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 isdetected 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 bebrought up to date with all immunisations, including prophylactic zoster vaccinations, in agreementwith current immunisation guidelines. (see section 5.1 for data on adjuvanted recombinantglycoprotein E herpes zoster vaccine and inactivated pneumococcal polysaccharide conjugate vaccine(13-valent, adsorbed) and concomitant use with upadacitinib).
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 rateof 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 othermalignancy 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
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 skinexamination 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 patientmanagement (see section 4.2).
Gastrointestinal perforations
Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and frompost-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 antiinflammatory drugs (NSAIDs), corticosteroids, or opioids). Patients with active
Crohn’s disease are at increased risk for developing intestinal perforation. Patients presenting withnew onset abdominal signs and symptoms should be evaluated promptly for early identification ofdiverticulitis or gastrointestinal perforation.
9

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 rateof 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.
LipidsTreatment 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 elevationcompared to placebo.
Evaluate 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, adose-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 for10changes in VTE risk. Promptly evaluate patients with signs and symptoms of VTE and discontinue
upadacitinib in patients with suspected VTE, regardless of dose.
Hypersensitivity reactions
Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients
receiving upadacitinib. If a clinically significant hypersensitivity reaction occurs, discontinue
upadacitinib and institute appropriate therapy (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 medication for diabetes. Dose adjustment of anti-diabetic
medication may be necessary in the event that hypoglycaemia occurs.
4.5

Interaction with other medicinal products and other forms of interaction

Potential for other medicinal products to affect the pharmacokinetics of upadacitinib
Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can beaffected by medicinal products that strongly inhibit or induce CYP3A4.
Coadministration 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 clinicalstudy, coadministration of upadacitinib with ketoconazole resulted in 70% and 75% increases inupadacitinib Cmax and AUC, respectively. Upadacitinib 15 mg once daily should be used with caution
in patients receiving chronic treatment with strong CYP3A4 inhibitors. Upadacitinib 30 mg once daily
dose is not recommended for patients with atopic dermatitis receiving chronic treatment with strong
CYP3A4 inhibitors. 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 maintenancedose is 15 mg once daily (see section 4.2). Alternatives to strong CYP3A4 inhibitor medications
should be considered when used in the long-term. Food or drink containing grapefruit should be
avoided during treatment with upadacitinib.
Coadministration with CYP3A4 inducers
Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such asrifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinicalstudy, 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 withstrong CYP3A4 inducers.
Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have noeffect 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 alimited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (24-26% decrease inmidazolam 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 C max was decreased by 23% following the administrationof 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
11

metabolite for atorvastatin). Administration of multiple 45 mg once daily doses of upadacitinib tohealthy 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 coadministered with upadacitinib.
Upadacitinib has no relevant effects on plasma exposures of ethinylestradiol, levonorgestrel,
methotrexate, or medicinal products that are substrates for metabolism by CYP1A2, CYP2B6,
CYP2C9, or CYP2C19.
4.6

Fertility, pregnancy and lactation

Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception during treatment
and for 4 weeks following the final dose of upadacitinib. Female paediatric patients and/or theirparents/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 haveshown reproductive toxicity (see section 5.3). Upadacitinib was teratogenic in rats and rabbits witheffects 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 (seesection 5.3).
A risk to newborns/infants cannot be excluded.
Upadacitinib should not be used during breast-feeding. A decision must be made whether todiscontinue breast-feeding or to discontinue upadacitinib therapy taking into account the benefit ofbreast-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).

12

4.7

Effects on ability to drive and use machines

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

Undesirable effects

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 theindications 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%), alaninetransaminase increased (4.3%), bronchitis (3.9%), nausea (3.5%), neutropaenia (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%), neutropaenia (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%), anemia (7.4%), headache (6.6%), acne (6.3%), herpes zoster (6.1%), neutropaenia (6.0%),
rash (5.2%), pneumonia (4.1%), hypercholesterolemia (4.0%), bronchitis (3.9%), aspartatetransaminase 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 experience from clinical studies.
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). The frequencies inTable 3 are based on the higher of the rates for adverse reactions reported with RINVOQ in clinical
trials of rheumatologic disease (15 mg), atopic dermatitis (15 mg and 30 mg), ulcerative colitis(15 mg, 30 mg and 45 mg), or Crohn’s disease (15 mg, 30 mg, and 45 mg). When notable differencesin frequency were observed between indications, these are presented in the footnotes below the table.

13

Table 3 Adverse reactions
System Organ Class
Infections andinfestations

Very common
Upper respiratory
tract infections(URTI)a

Neoplasms benign,malignant andunspecified (including
cysts and polyps)
Blood and lymphatic
system disorders

Anaemiaa
Neutropaenia a
Lymphopaenia
Urticariac,gImmune systemdisorders
Metabolism andnutrition disorders
Nervous systemdisorders
Ear and labyrinth
disorders
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disordersSkin and subcutaneous
tissue disorders
General disorders andadministration site
conditions
Investigations

CommonBronchitisa,bHerpes zoster aHerpes simplexa
Folliculitis
Influenza
Urinary tract infection
Pneumoniaa,hNon-melanoma skincancerf

Hypercholesterolaemia a,b

UncommonOral candidiasis
Diverticulitis
SepsisSerious hypersensitivity
reactionsa,eHypertriglyceridaemia

Hyperlipidaemia a,b
Headachea
Dizziness
Vertigoa
Cough

Acnea,c,d,g

Abdominal paina,dNauseaRasha

Gastrointestinal
perforationi

FatiguePyrexia
Blood CPK increased
ALT increasedb
AST increasedb
Weight increasedgaPresented as grouped term
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.
dIn ulcerative colitis trials, the frequency was common for acne; abdominal pain was less frequent for
upadacitinib than for placebo.
eSerious hypersensitivity reactions including anaphylactic reaction and angioedemaf
Most events reported as basal cell carcinoma and squamous cell carcinoma of sking
In Crohn’s disease, the frequency was common for acne, and uncommon for urticaria and weightincreased.
hPneumonia was common in Crohn’s disease and uncommon across other indications.
iFrequency is based on Crohn’s disease clinical trials.
b

14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 theupadacitinib 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 rateof 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 theplacebo 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 longterm rate of opportunistic infections for the upadacitinib 15 mg group across all five Phase 3 clinicalstudies 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 clinicalstudies 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, comparedto 1.5% and 0.7%, respectively, of patients treated with placebo. Most cases of hepatic transaminase
elevations 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, comparedto 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 totalcholesterol, 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 withlonger-term treatment. Among patients in the controlled studies with baseline values below thespecified limits, the following frequencies of patients were observed to shift to above the specified

15

limits on at least one occasion during 12/14 weeks (including patients who had an isolated elevatedvalue):••••

Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 62% vs. 31%, in the upadacitinib 15 mg andplacebo groups, respectively
LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 42% vs. 19%, in the upadacitinib 15 mg andplacebo groups, respectively
HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 89% vs. 61%, in the upadacitinib 15 mg andplacebo groups, respectively
Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 25% vs. 15%, in the upadacitinib 15 mg and placebogroups, 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% and0.3% 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 anincreased value thereafter including with extended therapy.
Neutropaenia
In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases inneutrophil 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 wasinterrupted 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% and0.4%, 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 withupadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid
arthritis. No new safety findings were identified.
Atopic dermatitis
Infections
In the placebo-controlled period of the clinical studies, the frequency of infection over 16 weeks in theupadacitinib 15 mg and 30 mg groups was 39% and 43% compared to 30% in the placebo group,
respectively. The long-term rate of infections for the upadacitinib 15 mg and 30 mg groups was 98.5
and 109.6 events per 100 patient-years, respectively.
In placebo-controlled clinical studies, the frequency of serious infection over 16 weeks in theupadacitinib 15 mg and 30 mg groups was 0.8% and 0.4% compared to 0.6% in the placebo group,16

respectively. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups
was 2.3 and 2.8 events per 100 patient-years, respectively.
Opportunistic infections (excluding tuberculosis)
In the placebo-controlled period of the clinical studies, all opportunistic infections (excluding TB andherpes zoster) reported were 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 placebogroup, respectively. The long-term rate of eczema herpeticum for the upadacitinib 15 mg and 30 mggroups was 1.6 and 1.8 events per 100 patient-years, respectively. One case of esophageal candidiasis
was reported with upadacitinib 30 mg.
The long-term rate of herpes zoster for the upadacitinib 15 mg and 30 mg groups was 3.5 and 5.2
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 neutropaenia (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.
Ulcerative colitis
The overall safety profile observed in patients with ulcerative colitis was generally consistent with thatobserved 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 theplacebo-controlled maintenance study, the frequency of infection over 52 weeks in the upadacitinib
15 mg and 30 mg groups was 38.4% and 40.6%, respectively, compared to 37.6% in the placebogroup. The long-term rate of infections for upadacitinib 15 mg and 30 mg was 73.8 and 82.6 events
per 100 patient-years, respectively.
In the placebo-controlled induction studies, the frequency of serious infection over 8 weeks in both theupadacitinib 45 mg group and the placebo group was 1.3%. No additional serious infections wereobserved 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 3.2% and 2.4%, respectively, compared to 3.3% in the placebo group. The longterm rate of serious infections for the upadacitinib 15 mg and 30 mg groups was 4.1 and 3.9 events per
100 patient-years, respectively. The most frequently reported serious infection in the induction andmaintenance 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 theplacebo group. No additional opportunistic infections (excluding tuberculosis and herpes zoster) wereobserved 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 and17herpes zoster) in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.4%, 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 0.6 and 0.3 events
per 100 patient-years, respectively.
In the placebo-controlled induction studies over 8 weeks, the frequency of herpes zoster in theupadacitinib 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 4.4%
and 4.0%, 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 5.7 and 6.3 events per 100 patient-years, respectively.
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 neutropaenia (ANC < 1 x 109 cells/L)
associated with upadacitinib treatment were generally similar to what was observed in therheumatologic disease and atopic dermatitis clinical studies. Dose-dependent changes for theselaboratory 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 occurredin 1.6%, 0.8% 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 (seesection 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 andremained 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, thefollowing 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 andplacebo groups, respectively
LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 27% vs. 9%, in the upadacitinib 45 mg andplacebo groups, respectively
HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 79% vs. 36%, in the upadacitinib 45 mg andplacebo groups, respectively
Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 6% vs 4% in the upadacitinib 45 mg and placebogroups, respectively

Crohn’s disease
Overall, the safety profile observed in patients with Crohn’s disease treated with upadacitinib wasconsistent with the known safety profile for upadacitinib.
Serious infections
In the placebo-controlled induction studies, the frequency of serious infection over 12 weeks in theupadacitinib 45 mg group and the placebo group was 1.9% and 1.7%, respectively. In theplacebo-controlled maintenance study, the frequency of serious infection over 52 weeks in theupadacitinib 15 mg and 30 mg groups was 3.2% and 5.7%, respectively, compared to 4.5% in theplacebo 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
18

patient-years, respectively. The most frequently reported serious infection in the induction andmaintenance 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 onplacebo 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 eachtreated with placebo (0.7 per 100 patient-years), upadacitinib 15 mg (0.4 per 100 patient-years), andupadacitinib 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) throughlong-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), neutropaenia (ANC < 1 x 109 cells/L), andlipid parameters associated with upadacitinib treatment were generally similar to what was observed in
the rheumatologic disease, atopic dermatitis and ulcerative colitis clinical studies. Dose-dependentchanges for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment wereobserved.
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 occurredin 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 (seesection 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 inthe 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 limited data in atopic dermatitis patients 65 years of age and older, there was a higher rate ofoverall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose.
Based on the limited data in ulcerative colitis and Crohn’s disease patients 65 years of age and older,
there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the
15 mg dose with maintenance treatment (see section 4.4).
Paediatric population
A total of 343 adolescents aged 12 to 17 years with atopic dermatitis were treated in the Phase 3
studies, of whom 167 were exposed to 15 mg. The safety profile for upadacitinib 15 mg in adolescents19

was similar to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being
investigated.
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.
4.9

Overdose

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 iseliminated within 24 hours of dosing (within the range of doses evaluated in clinical studies). In caseof 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

5.1

Pharmacodynamic 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 withfunctional 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 signaling of many
mediators which drive the signs and symptoms of atopic dermatitis such as eczematous skin lesions
and pruritus. 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 adose- 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.
20

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 frombaseline 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 prevaccination 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.
The influence of upadacitinib on the humoral response following the administration of inactivatedpneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) was evaluated in 111 patientswith rheumatoid arthritis under stable treatment with upadacitinib 15 mg (n=87) or 30 mg (n=24). 97%
of patients (n=108) were on concomitant methotrexate. The primary endpoint was the proportion ofpatients with satisfactory humoral response defined as ≥ 2-fold increase in antibody concentrationfrom baseline to week 4 in at least 6 out of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14,
18C, 19A, 19F, and 23F). Results at week 4 demonstrated a satisfactory humoral response in 67.5%(95% CI: 57.4, 77.5) and 56.5% (95% CI: 36.3, 76.8) of patients treated with upadacitinib 15 mg and
30 mg, respectively.
Clinical efficacy and safety
Rheumatoid arthritis
The efficacy and safety of upadacitinib 15 mg once daily was assessed in five Phase 3 randomised,double-blind, multicentre studies in patients with moderately to severely active rheumatoid arthritis
and fulfilling the ACR/EULAR 2010 classification criteria (see Table 4). Patients 18 years of age andolder were eligible to participate. The presence of at least 6 tender and 6 swollen joints and evidenceof systemic inflammation based on elevation of hsCRP was required at baseline. Four studies included
long-term extensions for up to 5 years, and one study (SELECT-COMPARE) included a long-term
extension for up to 10 years.
The primary analysis for each of these studies included all randomised subjects who received at least 1
dose of upadacitinib or placebo, and non-responder imputation was used for categorical endpoints.
Across the Phase 3 studies, the efficacy seen with upadacitinib 15 mg QD was generally similar to thatobserved with upadacitinib 30 mg QD.
Table 4 Clinical trials summary
Study namePopulation (n)Treatment arms

21

Key outcome measures

SELECT-EARLY

MTX-naïvea
(947)• Upadacitinib 15 mg• Upadacitinib 30 mg• MTX
Monotherapy

SELECTMONOTHERAPY

MTX-IRb(648)• Upadacitinib 15 mg• Upadacitinib 30 mg• MTX
Monotherapy

SELECT-NEXT

csDMARD-IRc(661)• Upadacitinib 15 mg• Upadacitinib 30 mg• Placebo
On background
csDMARDs

SELECTCOMPARE

MTX-IRd(1,629)• Upadacitinib 15 mg• Placebo• Adalimumab 40 mg
On background MTX

SELECTBEYOND

bDMARD-IRe(499)• Upadacitinib 15 mg• Upadacitinib 30 mg• Placebo
On background
csDMARDs

22• Primary endpoint: clinical remission(DAS28-CRP) at week 24• Low disease activity (DAS28-CRP)• ACR50• Radiographic progression (mTSS)• Physical function (HAQ-DI)• SF-36 PCS• Primary endpoint: low disease activity(DAS28-CRP) at week 14• Clinical remission (DAS28-CRP)• ACR20• Physical function (HAQ-DI)• SF-36 PCS• Morning stiffness• Primary endpoint: low disease activity(DAS28-CRP) at week 12• Clinical remission (DAS28-CRP)• ACR20• Physical function (HAQ-DI)• SF-36 PCS• Low disease activity (CDAI)• Morning stiffness• FACIT-F• Primary endpoint: clinical remission(DAS28-CRP) at week 12• Low disease activity (DAS28-CRP)• ACR20• Low disease activity (DAS28-CRP) vsadalimumab• Radiographic progression (mTSS)• Physical function (HAQ-DI)• SF-36 PCS• Low disease activity (CDAI)• Morning stiffness• FACIT-F• Primary endpoint: low disease activity(DAS28-CRP) at week 12• ACR20• Physical function (HAQ-DI)• SF-36 PCS

Abbreviations: ACR20 (or 50) = American College of Rheumatology ≥20% (or ≥50%) improvement; bDMARD =biologic disease-modifying anti-rheumatic drug, CRP = C-Reactive Protein, DAS28 = Disease Activity Score 28 joints,
mTSS = modified Total Sharp Score, csDMARD = conventional synthetic disease-modifying anti-rheumatic drug,
HAQ-DI = Health Assessment Questionnaire-Disability Index, SF-36 PCS = Short Form (36) Health Survey (SF-36)
Physical Component Summary, CDAI = Clinical Disease Activity Index, FACIT-F = Functional Assessment ofChronic Illness Therapy-Fatigue score, IR = inadequate responder, MTX = methotrexate, n = number randomiseda.
Patients were naïve to MTX or received no more than 3 weekly MTX dosesbPatients had inadequate response to MTX
cPatients who had an inadequate response to csDMARDs; patients with prior exposure to at most one bDMARD were
eligible (up to 20% of total number of patients) if they had either limited exposure (<3 months) or had to discontinue
the bDMARD due to intolerabilitydPatients who had an inadequate response to MTX; patients with prior exposure to at most one bDMARD (except
adalimumab) were eligible (up to 20% of total study number of patients) if they had either limited exposure (<3months) or had to discontinue the bDMARD due to intolerabilityePatients who had an inadequate response or intolerance to at least one bDMARD

Clinical response
Remission and low disease activity
In the studies, a significantly higher proportion of patients treated with upadacitinib 15 mg achieved
low disease activity (DAS28-CRP ≤3.2) and clinical remission (DAS28-CRP <2.6) compared toplacebo, MTX, or adalimumab (Table 5). Compared to adalimumab, significantly higher rates of low
disease activity were achieved at week 12 in SELECT-COMPARE. Overall, both low disease activity
and clinical remission rates were consistent across patient populations, with or without MTX. At
3 years, 297/651 (45.6%) and 111/327 (33.9%) patients remained on originally randomised treatmentof upadacitinib 15 mg or adalimumab, respectively, in SELECT-COMPARE, and 216/317 (68.1%)
and 149/315 (47.3%) patients remained on originally randomised treatment of upadacitinib 15 mg or
MTX monotherapy, respectively, in SELECT-EARLY. Among the patients who remained on their
originally allocated treatment, low disease activity and clinical remission were maintained through3 years.
ACR response
In all studies, more patients treated with upadacitinib 15 mg achieved ACR20, ACR50, and ACR70
responses at 12 weeks compared to placebo, MTX, or adalimumab (Table 5). Time to onset of efficacy
was rapid across measures with greater responses seen as early as week 1 for ACR20. Durable
response rates were observed (with or without MTX), with ACR20/50/70 responses maintained
through 3 years among the patients who remained on their originally allocated treatment.
Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted in
improvements in individual ACR components, including tender and swollen joint counts, patient andphysician global assessments, HAQ-DI, pain assessment and hsCRP.
Table 5 Response and remission

Study

N
Week
a

b

12 /1424c/26d

SELECT
EARLY
MTX-Naїve
UPA
MTX 15mg
314
317

28
32

g

53
60f

SELECTMONO
MTX-IRUPA
MTX 15mg
216
217

SELECTNEXT
csDMARD-IR
UPA
PBO
15mg
221
221

SELECT
COMPAREMTX-IRUPA ADAPBO 15mg 40mg
651
651
327

LDA DAS28-CRP ≤3.2 (% of patients)
19
45e
17
48e
14
45e,h
18
55g,h
23

29
39

SELECT
BEYONDbDMARD-IR
UPA
PBO
15mg
169
164

14

43e

39

59g

b

12 /1424c/26d
48

14
18
29

g

36
48e
49g

12a/14b24c/26d
48

54
59
57

76g
79g
74g

12a/14b24c/26d

28
33

52g
60e

CR DAS28-CRP <2.6 (% of patients)
8
28e
10
31e
6
29e,h
9
41g,h
38i
ACR20 (% of patients)
41
68e
36
64e
36
71e,j
36
67g,i
65i
ACR50 (% of patients)
15
42g
15
38g
15
45g,h
21
54g,h

48

43

63g

49i

40

14
18
29

g

25g,h
35g,h
36h

13
23
23

48
a

a

b

12 /1424c/26d
48

32
44g
51g

50h

3

ACR70 (% of patients)
23g
6
21g
5
10

35
18
27
28

9

29g

63
57
54

28

65e

29
42

12

34g

7

12

CDAI ≤10 (% of patients)
12a/14b
30
46g
25
35l
19
40e
16
40e,h
30
14
32g
24c/26d
38
56g
22
53g,h
38
g
48
43
60
47h
34
Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or ≥70%)
improvement; ADA = adalimumab; CDAI = Clinical Disease Activity Index; CR = Clinical Remission;
CRP = C-Reactive Protein, DAS28 = Disease Activity Score 28 joints; IR = inadequate responder; LDA =Low Disease Activity; MTX = methotrexate; PBO = placebo; UPA= upadacitiniba
SELECT-NEXT, SELECT-EARLY, SELECT-COMPARE, SELECT-BEYONDb
SELECT-MONOTHERAPYc
SELECT-EARLYd
SELECT-COMPAREemultiplicity-controlled p≤0.001upadacitinib vs placebo or MTX comparisonfmultiplicity-controlled p≤0.01 upadacitinib vs placebo or MTX comparisongnominal p≤0.001 upadacitinib vs placebo or MTX comparisonhnominal p≤0.001upadacitinib vs adalimumab comparisoninominal p≤0.01 upadacitinib vs adalimumab comparisonjnominal p<0.05 upadacitinib vs adalimumab comparisonknominal p≤0.01 upadacitinib vs placebo or MTX comparisonlnominal p<0.05 upadacitinib vs MTX comparison
Note: Week 48-data derived from analysis on Full Analysis set (FAS) by randomised group using NonResponder Imputation
Radiographic response
Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score(mTSS) and its components, the erosion score and joint space narrowing score, at weeks 24/26 andweek 48 in SELECT-EARLY and SELECT-COMPARE.
Treatment with upadacitinib 15 mg resulted in significantly greater inhibition of the progression of
structural joint damage compared to placebo in combination with MTX in SELECT-COMPARE andas monotherapy compared to MTX in SELECT-EARLY (Table 6). Analyses of erosion and joint
space narrowing scores were consistent with the overall scores. The proportion of patients with noradiographic progression (mTSS change ≤ 0) was significantly higher with upadacitinib 15 mg in bothstudies. Inhibition of progression of structural joint damage was maintained through week 96 in bothstudies for patients who remained on their originally allocated treatment with upadacitinib 15 mg
24(based on available results from 327 patients in SELECT-COMPARE and 238 patients in SELECTEARLY).
Table 6 Radiographic changes
SELECT
SELECT
EARLY
COMPAREStudy
MTX-Naїve
MTX-IR
UPA
UPA
ADA
a
Treatment Group
MTX
15 mg
PBO
15 mg
40 mg
Modified Total Sharp Score, mean change from baseline
Week 24b/26c
0.7
0.1f
0.9
0.2g
0.1
e
e
Week 48
1.0
0.03
1.7
0.3
0.4
Proportion of patients with no radiographic progressiond
Week 24b/26c
77.7
87.5f
76.0
83.5f
86.8
e
e
Week 48
74.3
89.9
74.1
86.4
87.9
Abbreviations: ADA = adalimumab; IR = inadequate responder; MTX = methotrexate; PBO = placebo;
UPA= upadacitinibaAll placebo data at week 48 derived using linear extrapolationb
SELECT-EARLYc
SELECT-COMPAREd
No progression defined as mTSS change ≤ 0
enominal p≤0.001 upadacitinib vs placebo or MTX comparisonfmultiplicity-controlled p≤0.01 upadacitinib vs placebo or MTX comparisongmultiplicity-controlled p≤0.001 upadacitinib vs placebo or MTX comparison
Physical function response and health-related outcomes
Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted in asignificantly greater improvement in physical function compared to all comparators as measured by
HAQ-DI (see Table 7). Improvement in HAQ-DI was maintained through 3 years for patients who
remained on their originally allocated treatment with upadacitinib 15 mg based on available resultsfrom SELECT-COMPARE and SELECT-EARLY.
Table 7 Mean change from baseline in HAQ-DIa,bStudy

SELECT
EARLY
MTX-Naїve

SELECTMONO
MTX-IR

SELECTNEXT
csDMARD-IR

SELECT
COMPAREMTX-IR

SELECT
BEYOND
BIO-IR

Treatment
UPA
UPA
UPA
UPA
ADA
UPA
group
MTX 15mg MTX 15mg
PBO
15mg PBO 15mg 40mg PBO 15mg
N
313
317
216
216
220
216
648
644
324
165
163
Baselinescore,
1.6
1.6
1.5
1.5
1.4
1.5
1.6
1.6
1.6
1.6
1.7
mean
Week
-0.5
-0.8h
-0.3
-0.7g
-0.3
-0.6g
-0.3
-0.6g,i
-0.5
-0.2
-0.4g
12c/14d
Week
-0.6
-0.9g
-0.3
-0.7h,i-0.6
24e/26f
Abbreviations: ADA = adalimumab; HAQ-DI = Health Assessment Questionnaire-Disability Index; IR =inadequate responder; MTX = methotrexate; PBO = placebo; UPA = upadacitinibaData shown are meanb
Health Assessment Questionnaire-Disability Index: 0=best, 3=worst; 20 questions; 8 categories:
dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
c
SELECT-EARLY, SELECT-NEXT, SELECT-COMPARE, SELECT-BEYOND
25

d

SELECT-MONOTHERAPYSELECT-EARLY
f
SELECT-COMPAREgmultiplicity-controlled p≤0.001 upadacitinib vs placebo or MTX comparisonhnominal p≤0.001 upadacitinib vs placebo or MTX comparisoninominal p≤0.01 upadacitinib vs adalimumab comparisone

In the studies SELECT-MONOTHERAPY, SELECT-NEXT, and SELECT-COMPARE, treatment
with upadacitinib 15 mg resulted in a significantly greater improvement in the mean duration ofmorning joint stiffness compared to placebo or MTX.
In the clinical studies, upadacitinib-treated patients reported significant improvements in patientreported quality of life, as measured by the Short Form (36) Health Survey (SF-36) PhysicalComponent Summary compared to placebo and MTX. Moreover, upadacitinib-treated patients
reported significant improvements in fatigue, as measured by the Functional Assessment of Chronic
Illness Therapy-Fatigue score (FACIT-F) compared to placebo.
Psoriatic arthritis
The efficacy and safety of upadacitinib 15 mg once daily were assessed in two Phase 3 randomised,double-blind, multicentre, placebo-controlled studies in patients 18 years of age or older withmoderately to severely active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender joints
and at least 3 swollen joints, and active plaque psoriasis or history of plaque psoriasis. For bothstudies, the primary endpoint was the proportion of patients who achieved an ACR20 response at week
12.
SELECT-PsA 1 was a 24-week trial in 1705 patients who had an inadequate response or intolerance toat least one non-biologic DMARD. At baseline, 1393 (82%) of patients were on at least one
concomitant non-biologic DMARD; 1084 (64%) of patients received concomitant MTX only; and 311(18%) of patients were on monotherapy. Patients received upadacitinib 15 mg or 30 mg once daily,
adalimumab, or placebo. At week 24, all patients randomised to placebo were switched to upadacitinib
15 mg or 30 mg once daily in a blinded manner. SELECT-PsA 1 included a long-term extension for
up to 5 years.
SELECT-PsA 2 was a 24-week trial in 642 patients who had an inadequate response or intolerance toat least one biologic DMARD. At baseline, 296 (46%) of patients were on at least one concomitantnon-biologic DMARD; 222 (35%) of patients received concomitant MTX only; and 345 (54%) ofpatients were on monotherapy. Patients received upadacitinib 15 mg or 30 mg once daily or placebo.
At week 24, all patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg once
daily in a blinded manner. SELECT-PsA 2 included a long-term extension for up to 3 years.
Clinical response
In both studies, a statistically significant greater proportion of patients treated with upadacitinib 15 mg
achieved ACR20 response compared to placebo at week 12 (Table 8). Time to onset of efficacy was
rapid across measures with greater responses seen as early as week 2 for ACR20.
Treatment with upadacitinib 15 mg resulted in improvements in individual ACR components,
including tender/painful and swollen joint counts, patient and physician global assessments, HAQ-DI,
pain assessment, and hsCRP compared to placebo.
In SELECT-PsA 1, upadacitinib 15 mg achieved non-inferiority compared to adalimumab in the
proportion of patients achieving ACR20 response at week 12; however, superiority to adalimumab
could not be demonstrated.

26

In both studies, consistent responses were observed alone or in combination with methotrexate forprimary and key secondary endpoints.
The efficacy of upadacitinib 15 mg was demonstrated regardless of subgroups evaluated including
baseline BMI, baseline hsCRP, and number of prior non-biologic DMARDs (≤ 1 or >1).
Table 8 Clinical response in SELECT-PsA 1 and SELECT-PsA 2
StudyTreatment GroupN
Week 12Difference fromplacebo (95% CI)
Week 24
Week 56
Week 12
Week 24
Week 56
Week 12
Week 24
Week 56
Week 12
Week 24
Week 56
Week 12
Week 24
Week 56
Week 12
Week 24
Week 56
Week 16
Week 24
Week 56
Week 16
Week 24
Week 56

SELECT-PsA 1
non-biologic DMARD-IR
PBO
UPA
ADA
15 mg
40 mg
423
429
429
ACR20, % of patients (95% CI)
36 (32, 41)
71 (66, 75)f
65 (61, 70)-

35 (28, 41)d,e
45 (40, 50)

SELECT-PsA 2
bDMARD-IR
PBO
UPA
15 mg
212
211
24 (18, 30)

33 (24, 42)d,e73 (69, 78)
67 (63, 72) 20 (15, 26)
74 (70, 79)
69 (64, 73)
ACR50, % of patients (95% CI)
13 (10, 17)
38 (33, 42)
38 (33, 42)
5 (2, 8)19 (15, 23)
52 (48, 57)
44 (40, 49)
9 (6, 13)60 (55, 64)
51 (47, 56)
ACR70, % of patients (95% CI)
2 (1, 4)16 (12, 19)
14 (11, 17)
1 (0, 1)
5 (3, 7)29 (24, 33)
23 (19, 27)
1 (0, 2)41 (36, 45)
31 (27, 36)
MDA, % of patients (95% CI)
6 (4, 9)25 (21, 29)
25 (21, 29)
4 (2, 7)
12 (9, 15)
37 (32, 41)e33 (29, 38)
3 (1, 5)45 (40, 50)
40 (35, 44)
Resolution of enthesitis (LEI=0), % of patients (95% CI)a33 (27, 39)
47 (42, 53)
47 (41, 53) 20 (14, 27)
32 (27, 39)
54 (48, 60)e47 (42, 53)
15 (9, 21)
59 (53, 65)
54 (48, 60)
Resolution of dactylitis (LDI=0), % of patients (95% CI)b42 (33, 51)
74 (66, 81)
72 (64, 80) 36 (24, 48)
40 (31, 48)
77 (69, 84)
74 (66, 82) 28 (17, 39)
75 (68, 82)
74 (66, 82)
PASI75, % of patients (95% CI)c21 (16, 27)
63 (56, 69)e53 (46, 60) 16 (10, 22)
27 (21, 33)
64 (58, 70)
59 (52, 65) 19 (12, 26)
65 (59, 72)
61 (55, 68)
PASI90, % of patients (95% CI)c
12 (8, 17)
38 (32, 45)
39 (32, 45)
8 (4, 13)17 (12, 22)
42 (35, 48)
45 (38, 52)
7 (3, 11)49 (42, 56)
47 (40, 54)27

57 (50, 64)

59 (53, 66)
60 (53, 66)
32 (26, 38)
38 (32, 45)
41 (34, 47)
9 (5, 12)19 (14, 25)
24 (18, 30)
17 (12, 22)
25 (19, 31)e29 (23, 36)
39 (31, 47)
43 (34, 51)
43 (34, 51)
64 (51, 76)
58 (45, 71)
51 (38, 64)
52 (44, 61)e54 (45, 62)
52 (44, 61)
35 (26, 43)
36 (28, 44)
41 (32, 49)

Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or≥70%) improvement, ADA = adalimumab; bDMARD = biologic disease-modifying antirheumatic drug; IR = inadequate responder; MDA = minimal disease activity; PASI75 (or 90) =≥75% (or ≥90%) improvement in Psoriasis Area and Severity Index; PBO = placebo; UPA=
upadacitinib
Patients who discontinued randomised treatment or were missing data at week of evaluation were
imputed as non-responders in the analyses. For MDA, resolution of enthesitis, and resolution of
dactylitis at week 24/56, the subjects rescued at week 16 were imputed as non-responders in theanalyses.
a

In patients with enthesitis at baseline (n=241, 270, and 265, respectively, for SELECT-PsA 1 andn=144 and 133, respectively, for SELECT-PsA 2)b
In patients with dactylitis at baseline (n=126, 136, and 127, respectively, for SELECT-PsA 1 andn=64 and 55, respectively, for SELECT-PsA 2)c
In patients with ≥ 3% BSA psoriasis at baseline (n=211, 214, and 211, respectively, for
SELECT-PsA 1 and n=131 and 130, respectively, for SELECT-PsA 2)dprimary endpointemultiplicity-controlled p≤0.001 upadacitinib vs placebo comparisonfmultiplicity-controlled p≤0.001 upadacitinib vs adalimumab comparison (non-inferiority test)
Radiographic response
In SELECT-PsA 1, inhibition of progression of structural damage was assessed radiographically andexpressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, theerosion score and the joint space narrowing score, at week 24.
Treatment with upadacitinib 15 mg resulted in statistically significant greater inhibition of the
progression of structural joint damage compared to placebo at week 24 (Table 9). Erosion and joint
space narrowing scores were consistent with the overall scores. The proportion of patients with noradiographic progression (mTSS change ≤ 0.5) was higher with upadacitinib 15 mg compared toplacebo at week 24.
Table 9 Radiographic changes in SELECT-PsA 1
Treatment Group

UPA
15 mg

PBO

ADA
40 mg

Modified Total Sharp Score, mean change from baseline (95% CI)
Week 24
0.25 (0.13, 0.36)-0.04 (-0.16, 0.07)c
0.01 (-0.11, 0.13)
aWeek 56
0.44 (0.29, 0.59)-0.05 (-0.20, 0.09)-0.06 (-0.20, 0.09)b
Proportion of patients with no radiographic progression , % (95% CI)
Week 24
Week 56a

92 (89, 95)

96 (94, 98)

95 (93, 97)

89 (86, 92)

97 (96, 99)

94 (92, 97)

Abbreviations: ADA = adalimumab; PBO = placebo; UPA= upadacitinibaAll placebo data at week 56 derived using linear extrapolationb
No progression defined as mTSS change ≤0.5cmultiplicity-controlled p≤0.001 upadacitinib vs placebo comparison
Physical function response and health-related outcomes
In SELECT-PsA 1, patients treated with upadacitinib 15 mg showed statistically significant
improvement from baseline in physical function as assessed by HAQ-DI at week 12 (-0.42 [95% CI: 0.47, -0.37]) compared to placebo (-0.14 [95% CI: -0.18, -0.09]); improvement in patients treated withadalimumab was -0.34 (95% CI: -0.38, -0.29). In SELECT-PsA 2, patients treated with upadacitinib
15 mg showed statistically significant improvement from baseline in HAQ-DI at week 12 (-0.30 [95%28

CI: -0.37, -0.24]) compared to placebo (-0.10 [95% CI: -0.16, -0.03]). Improvement in physicalfunction was maintained through week 56 in both studies.
Health-related quality of life was assessed by SF-36v2. In both studies, patients receiving upadacitinib
15 mg experienced statistically significant greater improvement from baseline in the PhysicalComponent Summary score compared to placebo at week 12. Improvements from baseline weremaintained through week 56 in both studies.
Patients receiving upadacitinib 15 mg experienced statistically significant improvement from baselinein fatigue, as measured by FACIT-F score, at week 12 compared to placebo in both studies.
Improvements from baseline were maintained through week 56 in both studies.
At baseline, psoriatic spondylitis was reported in 31% and 34% of patients in SELECT-PsA 1 andSELECT-PsA 2, respectively. Patients with psoriatic spondylitis treated with upadacitinib 15 mg
showed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity Index(BASDAI) scores compared to placebo at week 24. Improvements from baseline were maintained
through week 56 in both studies.
Axial spondyloarthritis
Non-radiographic axial spondyloarthritis
The efficacy and safety of upadacitinib 15 mg once daily were assessed in a randomised, double-blind,multicentre, placebo-controlled study in patients 18 years of age or older with active non-radiographic
axial spondyloarthritis. Study SELECT-AXIS 2 (nr-axSpA) was a 52-week placebo-controlled trial in
314 patients with active non-radiographic axial spondyloarthritis with an inadequate response to atleast two NSAIDs or intolerance to or contraindication for NSAIDs. Patients must have had objective
signs of inflammation indicated by elevated C-reactive protein (CRP) (defined as > upper limit of
normal), and/or sacroiliitis on magnetic resonance imaging (MRI), and no definitive radiographic
evidence of structural damage on sacroiliac joints. Patients had active disease as defined by the BathAnkylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, and a Patient's Assessment of Total
Back Pain score ≥ 4 based on a 0 – 10 numerical rating scale (NRS) at the Screening and Baseline
Visits. At baseline, patients had symptoms of non-radiographic axial spondyloarthritis for an averageof 9.1 years and 29.1% of the patients were on a concomitant csDMARD. 32.9% of the patients had an
inadequate response or intolerance to bDMARD therapy. Patients received upadacitinib 15 mg once
daily or placebo. At week 52, all patients randomised to placebo were switched to upadacitinib 15 mg
once daily. The primary endpoint was the proportion of patients achieving an Assessment ofSpondyloArthritis international Society 40 (ASAS40) response at week 14. The study included a longterm extension for up to 2 years. Of patients who were initially randomised to upadacitinib, 75%(117/156) in SELECT-AXIS 2 (nr-axSpA) continued therapy through 2 years.
Clinical response
In SELECT-AXIS 2 (nr-axSpA), a significantly greater proportion of patients treated withupadacitinib 15 mg achieved an ASAS40 response compared to placebo at week 14 (Table 10).
A numerical difference between treatment groups was observed at all timepoints from week 2 to week
14.
Treatment with upadacitinib 15 mg resulted in improvements in individual ASAS components (patient
global assessment of disease activity, total back pain assessment, inflammation, and function) andother measures of disease activity, including hsCRP, compared to placebo at week 14.
The efficacy of upadacitinib 15 mg was demonstrated across subgroups including gender, baseline
BMI, symptom duration of non-radiographic axial spondyloarthritis, baseline hsCRP, MRI sacroiliitis,and prior use of bDMARDs.

29

Table 10 Clinical response in SELECT-AXIS 2 (nr-axSpA)
Treatment GroupNPBO
UPA 15 mg
157
156
a
ASAS40, % of patients (95% CI)
Week 1422.5 (16.0, 29.1)
44.9 (37.1, 52.7)
Difference from placebo (95% CI)
22.2 (12.1, 32.3)b
Week 52
42.7 (34.9, 50.4)
62.8 (55.2, 70.4)daASAS20, % of patients (95% CI)
Week 1443.8 (36.0, 51.5)
66.7 (59.3, 74.1)b
ASAS Partial Remission, % of patients (95% CI)
Week 147.6 (3.5, 11.8)
18.6 (12.5, 24.7)c
BASDAI 50, % of patients (95% CI)
Week 1422.1 (15.5, 28.6)
42.3 (34.6, 50.1)b
Change from baseline in ASDAS-CRP (95% CI)
Week 14-0.71 (-0.85, -0.56)-1.36 (-1.50, -1.21)b
ASDAS Inactive Disease, % of patients (95% CI)
Week 145.2 (1.7, 8.7)
14.1 (8.6, 19.6)c
ASDAS Low Disease Activity, % of patients (95% CI)
Week 1418.3 (12.2, 24.4)
42.3 (34.6, 50.1)bAbbreviations: ASAS20 (or ASAS40) = Assessment of SpondyloArthritis international Society ≥20%(or ≥40%) improvement; ASDAS-CRP = Ankylosing Spondylitis Disease Activity Score C-Reactive
Protein; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; PBO = placebo; UPA=
upadacitiniba
An ASAS20 (ASAS40) response is defined as a ≥20% (≥40%) improvement and an absolute
improvement from baseline of ≥1 (≥2) unit(s) (range 0 to 10) in ≥3 of 4 domains (Patient Global,
Total Back Pain, Function, and Inflammation), and no worsening in the potential remaining
domain (defined as worsening ≥20% and ≥1 unit for ASAS20 or defined as worsening of > 0 units for
ASAS40).
b
multiplicity-controlled p≤0.001 upadacitinib vs placebo comparisoncmultiplicity-controlled p≤0.01 upadacitinib vs placebo comparisondNominal p≤0.001 for upadacitinib vs placebo comparison, according to prespecified multiplicitycontrolled testing sequence
For binary endpoints, results are based on non-responder imputation in conjunction with multiple
imputation. For continuous endpoints, results are based on the least squares mean change frombaseline using mixed-effect models repeated measures analysis.
Efficacy was maintained through 2 years as assessed by the endpoints presented in Table 10.
Physical function response and health-related outcomes
Patients treated with upadacitinib 15 mg showed significant improvement in physical function frombaseline compared to placebo as assessed by the BASFI at week 14.
Patients treated with upadacitinib 15 mg showed significant improvements in total back pain andnocturnal back pain compared to placebo at week 14.
Patients treated with upadacitinib 15 mg showed significant improvements in health-related quality oflife and overall health as measured by ASQoL and ASAS Health Index, respectively, compared toplacebo at week 14.
Improvements in BASFI, total and nocturnal back pain, ASQoL and ASAS Health Index weremaintained through 2 years.
30

Objective measure of inflammation
Signs of inflammation were assessed by MRI and expressed as change from baseline in theSpondyloarthritis Research Consortium of Canada (SPARCC) score of the sacroiliac joints. At week
14, significant improvement of inflammatory signs in the sacroiliac joints was observed in patientstreated with upadacitinib 15 mg compared to placebo. Improvement in inflammation as assessed by
MRI was maintained through 2 years.
Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)
The efficacy and safety of upadacitinib 15 mg once daily were assessed in two randomised,double-blind, multicentre, placebo-controlled studies in patients 18 years of age or older with active
ankylosing spondylitis based upon the Bath Ankylosing Spondylitis Disease Activity Index(BASDAI) ≥4 and Patient’s Assessment of Total Back Pain score ≥4. Both studies included along-term extension for up to 2 years.
SELECT-AXIS 1 was a 14-week placebo-controlled trial in 187 ankylosing spondylitis patients withan inadequate response to at least two NSAIDs or intolerance to or contraindication for NSAIDs andhad no previous exposure to biologic DMARDs. At baseline, patients had symptoms of ankylosing
spondylitis for an average of 14.4 years and approximately 16% of the patients were on a concomitantcsDMARD. Patients received upadacitinib 15 mg once daily or placebo. At week 14, all patientsrandomised to placebo were switched to upadacitinib 15 mg once daily. The primary endpoint was the
proportion of patients achieving an Assessment of SpondyloArthritis international Society 40(ASAS40) response at week 14.
SELECT-AXIS 2 (AS) was a 14-week placebo-controlled trial in 420 ankylosing spondylitis patientswith prior exposure to bDMARDs (77.4% had lack of efficacy to either a TNF inhibitor or interleukin17 inhibitor (IL-17i); 30.2% had intolerance; 12.9% had prior exposure but not lack of efficacy to two
bDMARDs). At baseline, patients had symptoms of ankylosing spondylitis for an average of 12.8
years and approximately 31% of the patients were on a concomitant csDMARD. Patients received
upadacitinib 15 mg once daily or placebo. At week 14, all patients randomised to placebo were
switched to upadacitinib 15 mg once daily. The primary endpoint was the proportion of patientsachieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week
14.
Of patients who were initially randomised to upadacitinib, 72% (67/93) in SELECT-AXIS 1 and 77%(163/211) in SELECT-AXIS 2 (AS) continued therapy through 2 years.
Clinical response
In both studies, a significantly greater proportion of patients treated with upadacitinib 15 mg achieved
an ASAS40 response compared to placebo at week 14 (Table 11). A numerical difference between
treatment groups was observed from week 2 in SELECT-AXIS 1 and week 4 in SELECT-AXIS 2(AS) for ASAS40.
Treatment with upadacitinib 15 mg resulted in improvements in individual ASAS components (patient
global assessment of disease activity, total back pain assessment, inflammation, and function) andother measures of disease activity, including hsCRP, at week 14 compared to placebo.
The efficacy of upadacitinib 15 mg was demonstrated regardless of subgroups evaluated including
gender, baseline BMI, symptom duration of AS, baseline hsCRP, and prior use of bDMARDs.

31

Table 11 Clinical response
Study
TreatmentGroup
N
Week 14
Difference fromplacebo (95%CI)
Week 14
Week 14
Week 14
Week 14
Week 14

SELECT-AXIS 1
bDMARD-naïvePBO
UPA 15 mg

SELECT-AXIS 2 (AS)bDMARD-IR
PBO
UPA 15 mg

94

93
209
ASAS40, % of patients (95% CI)a,b
25.5 (16.7, 34.3) 51.6 (41.5, 61.8) 18.2 (13.0, 23.4)
26.1 (12.6, 39.5)c211
44.5 (37.8, 51.3)

26.4 (17.9, 34.9)c

ASAS20, % of patients (95% CI)a40.4 (30.5, 50.3)
64.5 (54.8,
38.3 (31.7, 44.9)
74.2)eASAS Partial Remission, % of patients (95% CI)
1.1 (0.0, 3.1)
19.4 (11.3,
4.3 (1.6, 7.1)
27.4)cBASDAI 50, % of patients (95% CI)
23.4 (14.8, 32.0)
45.2 (35.0,
16.7 (11.7, 21.8)
55.3)dChange from baseline in ASDAS-CRP (95% CI)-0.54 (-0.71, -1.45 (-1.62, -0.49 (-0.62, 0.37)1.28)c0.37)
ASDAS Inactive Disease, % of patients (95% CI)
016.1 (8.7, 23.6)e
1.9 (0.1, 3.8)

65.4 (59.0, 71.8)c
17.5 (12.4, 22.7)c
43.1 (36.4, 49.8)c-1.52 (-1.64, -1.39)c
12.8 (8.3, 17.3)c

ASDAS Low Disease Activity, % of patients (95% CI)
10.6 (4.4, 16.9)
49.5 (39.3,
10.1 (6.0, 14.2)
44.1 (37.4, 50.8)cf
59.6)
ASDAS Major Improvement, % of patients (95% CI)
Week 145.3 (0.8, 9.9)
32.3 (22.8,
4.8 (1.9, 7.7)
30.3 (24.1, 36.5)e
e
41.8)
a
An ASAS20 (ASAS40) response is defined as a ≥20% (≥40%) improvement and an absolute
improvement from baseline of ≥1 (≥2) unit(s) (range 0 to 10) in ≥3 of 4 domains (Patient Global,
Total Back Pain, Function, and Inflammation), and no worsening in the potential remaining
domain (defined as worsening ≥20% and ≥1 unit for ASAS20 or defined as worsening of > 0 units
for ASAS40).
b
primary endpointcmultiplicity-controlled p≤0.001 upadacitinib vs placebo comparisondmultiplicity-controlled p≤0.01 upadacitinib vs placebo comparisonecomparison not multiplicity-controlledfpost-hoc analysis for SELECT-AXIS 1, not multiplicity-controlled
For binary endpoints, week 14 results are based on non-responder imputation (SELECT-AXIS 1)
and on non-responder imputation in conjunction with multiple imputation (SELECT-AXIS 2 [AS]).
For continuous endpoints, week 14 results are based on the least squares mean change from baseline
using mixed models for repeated measures analysis.
Week 14

In both studies, efficacy was maintained through 2 years as assessed by the endpoints presented inTable 11.

32

Physical function response and health-related outcomes
In both studies, patients treated with upadacitinib 15 mg showed significant improvement in physicalfunction from baseline compared to placebo as assessed by the Bath Ankylosing Spondylitis
Functional Index (BASFI) change from baseline at week 14. Improvement in BASFI was maintained
through 2 years.
In SELECT-AXIS 2 (AS), patients treated with upadacitinib 15 mg showed significant improvements
in total back pain and nocturnal back pain compared to placebo at week 14. Improvements in total
back pain and nocturnal back pain were maintained through 2 years.
In SELECT-AXIS 2 (AS), patients treated with upadacitinib 15 mg showed significant improvements
in health-related quality of life and overall health as measured by ASQoL and ASAS Health Index,
respectively, compared to placebo at week 14. Improvements in ASQoL and ASAS Health Index weremaintained through 2 years.
Enthesitis
In SELECT-AXIS 2 (AS), patients with pre-existing enthesitis (n=310) treated with upadacitinib
15 mg showed significant improvement in enthesitis compared to placebo as measured by change frombaseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at week 14. Improvement inenthesitis was maintained through 2 years.
Spinal mobility
In SELECT-AXIS 2 (AS), patients treated with upadacitinib 15 mg showed significant improvementin spinal mobility compared to placebo as measured by change from baseline in Bath Ankylosing
Spondylitis Metrology Index (BASMI) at week 14. Improvement in BASMI was maintained through2 years.
Objective measure of inflammation
Signs of inflammation were assessed by MRI and expressed as change from baseline in the SPARCC
score for spine. In both studies at week 14, significant improvement of inflammatory signs in the spine
was observed in patients treated with upadacitinib 15 mg compared to placebo. Improvement ininflammation as assessed by MRI was maintained through 2 years.
Atopic dermatitis
The efficacy and safety of upadacitinib 15 mg and 30 mg once daily was assessed in three Phase 3
randomised, double-blind, multicentre studies (MEASURE UP 1, MEASURE UP 2 and AD UP) in a
total of 2584 patients (12 years of age and older). Upadacitinib was evaluated in 344 adolescent and
2240 adult patients with moderate to severe atopic dermatitis (AD) not adequately controlled by
topical medication(s). At baseline, patients had to have all the following: an Investigator's Global
Assessment (vIGA-AD) score ≥ 3 in the overall assessment of AD (erythema, induration/papulation,and oozing/crusting) on an increasing severity scale of 0 to 4, an Eczema Area and Severity Index(EASI) score ≥16 (composite score assessing extent and severity of erythema, oedema/papulation,scratches and lichenification across 4 different body sites), a minimum body surface area (BSA)
involvement of ≥ 10%, and weekly average Worst Pruritus Numerical Rating Scale (NRS) ≥ 4.
In all three studies, patients received upadacitinib once daily doses of 15 mg, 30 mg, or matchingplacebo for 16 weeks. In the AD UP study, patients also received concomitant topical corticosteroids(TCS). Following completion of the double blinded period, patients originally randomised toupadacitinib were to continue receiving the same dose until week 260. Patients in the placebo groupwere re-randomised in a 1:1 ratio to receive upadacitinib 15 mg or 30 mg until week 260.
33

Baseline characteristics
In the monotherapy studies (MEASURE UP 1 and 2), 50.0% of patients had a baseline vIGA-AD
score of 3 (moderate) and 50.0% of patients had a baseline vIGA-AD of 4 (severe). The mean baseline
EASI score was 29.3 and the mean baseline weekly average Worst Pruritus NRS was 7.3. In theconcomitant TCS study (AD UP), 47.1% of patients had a baseline vIGA-AD score of 3 (moderate)
and 52.9% of patients had a baseline vIGA-AD of 4 (severe). The mean baseline EASI score was 29.7
and the mean baseline weekly average Worst Pruritus NRS was 7.2.
Clinical response
Monotherapy (MEASURE UP 1 AND MEASURE UP 2) and Concomitant TCS (AD UP) studies
A significantly greater proportion of patients treated with upadacitinib 15 mg or 30 mg achieved
vIGA-AD 0 or 1, EASI 75, or a ≥ 4-point improvement on the Worst Pruritus NRS compared toplacebo at week 16. Rapid improvements in skin clearance and itch were also achieved (see Table 12).
Figure 1 shows the proportion of patients achieving an EASI 75 response and mean percent change
from baseline in Worst Pruritus NRS, respectively up to week 16 for MEASURE UP 1 and 2.
Table 12 Efficacy results of upadacitinib
Study
Treatment
Group
Number of
subjects
randomised

MEASURE UP 1
PBO
UPA
UPA
15 mg
30 mg

MEASURE UP 2
PBO
UPA
UPA
15 mg
30 mg

PBO +
TCS

AD UP
UPA
UPA
15 mg 30 mg +
+ TCS
TCS

281

278

276

282

304

300

297

5
(2,7)

39d
(33,45)52d(46,58)11(7,14)

40d(34,45)59d(53,64)13(9,17)

60d(54,66)73d(68,78)26(21,31)65d(59,70)77d(72,82)281

285

Week 16 endpoints, % responders (95% CI)
vIGA-AD848d62d0/1a,b(5,12)(42,54)(56,68)(co-primary)
EASI 75a1670d
80d(co-primary)(12,21) (64,75)(75,84)
EASI 90a8(5,11)

53d(47,59)66d(60,71)

5
(3,8)

42d
(37,48)58d(53,64)13(9,17)

43d(37,48)63d(58,69)EASI 100a

2
(0,3)

17d
(12,21)27d(22,32)

1
(0,2)

14d
(10,18)19d(14,23)

1
(0,3)

12e
(8,16)

23d(18,27)

Worst Pruritus
12
52d
60d
9
c
NRS
(8,16)(46,58)(54,66)(6,13)(≥ 4-point
improvement)
Early onset endpoints, % responders (95% CI)
EASI 75a
4
38d
47d
4
(Week 2)
(1,6)
(32,44)(42,53)(1,6)
Worst Pruritus
0
15d
20d
1
NRS
(0,1)
(11,19)(15,24)(0,2)

42d(36,48)60d(54,65)

15(11,19)52d(46,58)64d(58,69)33d(27,39)7d(4,11)

44d(38,50)16d(11,20)

7(4,10)
3(1,5)

31d(26,36)12d(8,16)

44d(38,50)19d(15,24)34

(≥ 4-point
improvement
at week 1)c,f
Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo
Subjects with rescue medication or with missing data were counted as non-responders. The number andpercentage of subjects who were imputed as non-responders for EASI 75 and vIGA-AD 0/1 at Week 16 due tothe use of rescue therapy in the placebo, upadacitinib 15 mg, and upadacitinib 30 mg groups, respectively, were132 (47.0%), 31 (11.0%), 16 (5.6%) in MEASURE UP 1, 119 (42.8%), 24 (8.7%), 16 (5.7%) in MEASURE
UP 2, and 78 (25.7%), 15 (5.0%), 14 (4.7%) in AD UP.
a
Based on number of subjects randomisedbResponder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2
points on a 0-4 ordinal scalecResults shown in subset of patients eligible for assessment (patients with Worst Pruritus NRS ≥ 4 at baseline)dStatistically significant vs. placebo with p < 0.001
ep < 0.001 vs placebo, without multiplicity controlfStatistically significant improvements vs placebo were seen as early as 1 day after initiating upadacitinib
30 mg and 2 days after initiating upadacitinib 15 mg in MEASURE UP 1 and 2
Figure 1 Proportion of patients achieving an EASI 75 response and mean percent change frombaseline in Worst Pruritus NRS in MEASURE UP 1 and MEASURE UP 2
Mean percent change from baseline in
Worst Pruritus NRS

Response Rate (%) and 95%
Confidence Interval

Percent Change from Baseline (%)
and 95% Confidence Interval

Proportion of patients achieving an
EASI 75 response

Weeks

Weeks

Placebo

Placebo

RINVOQ 15 mg QD

RINVOQ 15 mg QD

RINVOQ 30 mg QD

RINVOQ 30 mg QD*: p < 0.001 vs placebo, without multiplicity control**: statistically significant vs. placebo with p < 0.001
Treatment effects in subgroups (weight, age, gender, race, and prior systemic treatment withimmunosuppressants) were consistent with the results in the overall study population.
Results at week 16 continued to be maintained through week 52 in patients treated with upadacitinib
15 mg or 30 mg.
Quality of life/patient-reported outcomes35

Table 13 Patient-reported outcomes results of upadacitinib at week 16
Study

MEASURE UP 1

MEASURE UP 2

Treatment group

PBO

UPA
15 mg

UPA
30 mg

PBO

UPA
15 mg

UPA
30 mg

Number of subjects
randomised

281

281

285

278

276

282

ADerm-SS Skin Pain(≥ 4-point improvement)a15(10,20)54 e(47,60)63e(57,69)13(9,18)

49e(43,56)65e(59,71)ADerm-IS Sleep(≥ 12-point improvement) a,b

13(9,18)

55e(48,62)66e(60,72)

12(8,17)

50e(44,57)62e(56,69)DLQI 0/1c

4
(2,7)

30e
(25,36)41e(35,47)

5
(2,7)

24e
(19,29)38e(32,44)

HADS Anxiety <8 and
HADS Depression < 8d

14
(8,20)

46e(37,54)49e(41,57)

11(6,17)

46e(38,54)56e(48,64)% responders (95% CI)

Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo; DLQI = Dermatology Life
Quality Index; HADS = Hospital Anxiety and Depression Scale
Subjects with rescue medication or with missing data were counted as non-responders.
The threshold values specified correspond to the minimal clinically important difference(MCID) and was used to determine response.
a
Results shown in subset of patients eligible for assessment (patients with assessment score >MCID at baseline).
b
ADerm-IS Sleep assesses difficulty falling asleep, sleep impact, and waking up at night due toAD.
cResults shown in subset of patients eligible for assessment (patients with DLQI > 1 atbaseline).
dResults shown in subset of patients eligible for assessment (patients with HADS Anxiety ≥ 8
or HADS Depression ≥ 8 at baseline)eStatistically significant vs. placebo with p < 0.001
Ulcerative colitis
The efficacy and safety of upadacitinib was evaluated in three multicentre, double-blind,placebo-controlled Phase 3 clinical studies: two replicate induction studies, UC-1 (U-ACHIEVE
Induction) and UC-2 (U-ACCOMPLISH), and a maintenance study UC-3 (U-ACHIEVE
Maintenance).
Disease activity was based on the adapted Mayo score (aMS, Mayo scoring system excluding
Physician's Global Assessment), which ranged from 0 to 9 and has three subscores that were eachscored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal bleeding subscore (RBS)
and a centrally-reviewed endoscopy subscore (ES).
Induction studies (UC-1 and UC-2)
In UC-1 and UC-2, 988 patients (473 and 515 patients, respectively) were randomised to upadacitinib
45 mg once daily or placebo for 8 weeks with a 2:1 treatment allocation ratio and included in theefficacy analysis. All enrolled patients had moderately to severely active ulcerative colitis defined as
an aMS of 5 to 9 with an ES of 2 or 3 and demonstrated prior treatment failure including inadequate
response, loss of response, or intolerance to prior conventional and/or biologic treatment. Prior36

treatment failure to at least 1 biologic therapy (prior biologic failure) was seen in 52% (246/473)
and 51% (262/515) of patients, respectively. Previous treatment failure to conventional therapy but notbiologics (without prior biologic failure) was seen in 48% (227/473) and 49% (253/515) of patients,
respectively.
At baseline in UC-1 and UC-2, 39% and 37% of patients received corticosteroids, 1.1% and 0.6% of
patients received methotrexate and 68% and 69% of patients received aminosalicylates. Concomitant
use of thiopurine was not allowed during the studies. Patient disease activity was moderate (aMS ≥5,≤7) in 61% and 60% of patients and severe (aMS >7) in 39% and 40% of patients.
The primary endpoint was clinical remission per aMS at week 8. Table 14 shows the primary and key
secondary endpoints including clinical response, mucosal healing, histologic-endoscopic mucosal
healing and deep mucosal healing.
Table 14 Proportion of patients meeting primary and key secondary efficacy endpoints at week 8
in the induction studies UC-1 and UC-2

Endpoint

UC-1(U-ACHIEVE)
UPATreatment
PBO
45 mg
Difference
N=154
N=319
(95% CI)

UC-2(U-ACCOMPLISH)
UPA
Treatment
PBO
45 mg
Difference
N=174
N=341
(95% CI)

Clinical remissiona

4.8%

4.1%

26.1%

21.6%*

33.5%(15.8, 27.4)

29.0%*(23.2, 34.7)

Prior biologic failure+

0.4%

17.9%

17.5%

2.4%

29.6%

Without prior biologic

9.2%

35.2%

26.0%

5.9%

37.5%

27.1%
31.6%

27.3%

72.6%

46.3%*

25.4%

74.5%

49.4%*+

failureClinical responseb(38.4, 54.2)(41.7, 57.1)

Prior biologic failure+

12.8%

64.4%

51.6%

19.3%

69.4%

50.1%

Without prior biologic

42.1%

81.8%

39.7%

31.8%

79.8%

48.0%

7.4%

36.3%

29.3%*

8.3%

44.0%

35.1%*

failure+Mucosal healingc(22.6, 35.9)(28.6, 41.6)

Prior biologic failure+

1.7%

27.0%

25.3%

4.8%

37.1%

32.3%

Without prior biologic

13.2%

46.8%

33.6%

12.0%

51.2%

39.2%

6.6%

30.1%

23.7%*

5.9%

36.7%

30.1%*+

failureHistologic-endoscopic
mucosal healingd(17.5, 30.0)(24.1, 36.2)

+

1.4%

22.7%

21.3%

4.6%

30.7%

26.1%

Without prior biologic

11.8%

38.2%

26.4%

7.2%

42.9%

35.7%

1.3%

10.7%

9.7%*

1.7%

13.5%

11.3%*

Prior biologic failure+

failureDeep mucosal healinge(5.7, 13.7)
Prior biologic failure+

0

6.5%

37

6.5%

(7.2, 15.3)
1.1%

9.2%

8.1%

Without prior biologic

2.6%

15.4%

12.8%

2.4%

17.9%

15.5%

failure+Abbreviations: PBO = placebo; UPA= upadacitinib; aMS = adapted Mayo Score, based on the Mayo
Scoring system (excluding Physician's Global Assessment), which ranged from 0 to 9 and has threesubscores that were each scored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal
bleeding subscore (RBS) and a centrally-reviewed endoscopy subscore (ES).
+The number of “Prior biologic failure” patients in UC-1 and UC-2 are 78 and 89 in the placebo group,and 168 and 173 in the upadacitinib 45 mg group, respectively; the number of “Without prior biologic
failure” patients in UC-1 and UC-2 are 76 and 85 in the placebo group, and 151 and 168 in theupadacitinib 45 mg group, respectively.
*
p <0.001, adjusted treatment difference (95% CI)a
Per aMS: SFS≤ 1 and not greater than baseline, RBS = 0, ES ≤ 1 without friabilityb
Per aMS: decrease ≥ 2 points and ≥ 30% from baseline and a decrease in RBS ≥ 1 from baseline or an
absolute RBS ≤ 1.
c
ES ≤ 1 without friabilitydES ≤ 1 without friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in < 5% of crypts,
no crypt destruction, and no erosions, ulcerations, or granulation tissue.)e
ES = 0, Geboes score < 2 (indicating no neutrophil in crypts or lamina propria and no increase ineosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue)
Disease activity and symptoms
The partial adapted Mayo score (paMS) is composed of SFS and RBS. Symptomatic response perpaMS is defined as a decrease of ≥1 point and ≥30% from baseline and a decrease in RBS ≥ 1 or an
absolute RBS ≤1. Statistically significant improvement compared to placebo per paMS was seen as
early as week 2 (UC-1: 60.1% vs 27.3% and UC-2: 63.3% vs 25.9%).
Extended induction
A total of 125 patients in UC-1 and UC-2 who did not achieve clinical response after 8 weeks oftreatment with upadacitinib 45 mg once daily entered an 8-week open-label extended induction period.
After the treatment of an additional 8 weeks (16 weeks total) of upadacitinib 45 mg once daily, 48.3%
of patients achieved clinical response per aMS. Among patients who responded to treatment of
16-week upadacitinib 45 mg once daily, 35.7% and 66.7% of patients maintained clinical response peraMS and 19.0% and 33.3% of patients achieved clinical remission per aMS at week 52 withmaintenance treatment of upadacitinib 15 mg and 30 mg once daily, respectively.
Maintenance study (UC-3)
The efficacy analysis for UC-3 was evaluated in 451 patients who achieved clinical response per aMS
with 8-week upadacitinib 45 mg once daily induction treatment. Patients were randomised to receive
upadacitinib 15 mg, 30 mg or placebo once daily for up to 52 weeks.
The primary endpoint was clinical remission per aMS at week 52. Table 15 shows the key secondary
endpoints including maintenance of clinical remission, corticosteroid-free clinical remission, mucosal
healing, histologic-endoscopic mucosal healing and deep mucosal healing.

38

Table 15 Proportion of patients meeting primary and key secondary efficacy endpoints at week
52 in the maintenance study UC-3

PBO
N=149

UPA
15 mg
N=148

UPA
30 mg
N=154

Clinical remissiona

12.1%

42.3%

51.7%

Prior biologic failure+
Without prior biologic failure+
Maintenance of clinicalremissionb

7.5%
17.6%
N = 5422.2%
N = 22
13.6%
N = 3228.1%
N = 5422.2%
N = 22
13.6%
N = 32
28.1%
14.5%

40.5%
43.9%
N = 4759.2%
N = 1776.5%
N = 3049.4%
N = 4757.1%
N = 17
70.6%
N = 30
49.4%
48.7%

49.1%
54.0%
N = 5869.7%
N = 2073.0%
N = 3868.0%
N = 5868.0%
N = 2073.0%
N = 3865.4%
61.6%

Prior biologic failure+
Without prior biologic failure+
Histologic-endoscopic
mucosal healinge
Prior biologic failure+
Without prior biologic failure+
Deep mucosal healingf

7.8%
22.5%
11.9%

43.3%
53.6%
35.0%

56.1%
66.6%
49.8%

5.2%
20.0%
4.7%

32.9%
36.9%
17.6%

47.6%
51.8%
19.0%

Prior biologic failure+
Without prior biologic failure+

2.5%
7.5%

17.2%
18.0%

16.1%
21.6%

Prior biologic failure
Without prior biologic failure
Corticosteroid-free clinicalremissionc
Prior biologic failure
Without prior biologic failure
Mucosal healingd

39

Treatment
Difference
15 mg vs PBO(95% CI)

Treatment
Difference
30 mg vs PBO(95% CI)

30.7%*(21.7, 39.8)
33.0%
26.3%
37.4%*(20.3, 54.6)

39.0%*(29.7, 48.2)
41.6%
36.3%
47.0%*(30.7, 63.3)

62.8%

59.4%

21.3%

39.9%

35.4%*(18.2, 52.7)
57.0%

45.1%*(28.7, 61.6)
59.4%

21.3%

37.2%

34.4%*(25.1, 43.7)
35.5%
31.1%
23.8%*(14.8, 32.8)
27.7%
16.9%
13.0%*(6.0, 20.0)
14.7%
10.6%

46.3%*(36.7, 55.8)
48.3%
44.1%
37.3%*(27.8, 46.8)
42.4%
31.8%
13.6%*(6.6, 20.6)
13.6%
14.2%

Abbreviations: PBO = placebo; UPA= upadacitinib; aMS = adapted Mayo Score, based on the Mayo Scoring
system (excluding Physician's Global Assessment), which ranged from 0 to 9 and has three subscores thatwere each scored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal bleeding subscore(RBS) and a centrally-reviewed endoscopy subscore (ES).
+The number of “Prior biologic failure” patients are 81, 71, and 73 in the placebo, upadacitinib 15 mg, and30 mg group, respectively. The number of “Without prior biologic failure” patients are 68, 77, and 81 in theplacebo, upadacitinib 15 mg, and 30 mg group, respectively.
* p <0.001, adjusted treatment difference (95% CI)a
Per aMS: SFS≤ 1 and not greater than baseline, RBS = 0, ES ≤ 1 without friabilitybClinical remission per aMS at Week 52 among patients who achieved clinical remission at the end of
induction treatment.
cClinical remission per aMS at Week 52 and corticosteroid-free for ≥90 days immediately preceding Week
52 among patients who achieved clinical remission at the end of the induction treatment.
dES ≤1 without friabilityeES ≤1 without friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt
destruction and no erosions, ulcerations or granulation tissue).
f
ES = 0, Geboes score < 2 (indicating no neutrophil in crypts or lamina propria and no increase in eosinophil,no crypt destruction, and no erosions, ulcerations or granulation tissue).
Disease symptoms
Symptomatic remission per paMS, defined as SFS ≤ 1 and RBS = 0, was achieved over time throughweek 52 in more patients treated with both upadacitinib 15 mg and 30 mg once daily compared withplacebo (Figure 2).

Percent Responders and 95%
Confidence Interval

Figure 2 Proportion of patients with symptomatic remission per partial adapted Mayo score overtime in maintenance study UC-3

Weeks
Placebo (N=149)

UPA 15 mg QD (N=148)

UPA 30 mg QD (N=154)

Endoscopic assessment
Endoscopic remission (normalisation of the endoscopic appearance of the mucosa) was defined as ESof 0. At week 8, a significantly greater proportion of patients treated with upadacitinib 45 mg once
daily compared to placebo achieved endoscopic remission (UC-1: 13.7% vs 1.3%, UC-2: 18.2% vs1.7%). In UC-3, a significantly greater proportion of patients treated with upadacitinib 15 mg and
30 mg once daily compared to placebo achieved endoscopic remission at week 52 (24.2% and 25.9%
vs 5.6%). Maintenance of mucosal healing at week 52 (ES ≤1 without friability) was seen in asignificantly greater proportion of patients treated with upadacitinib 15 mg and 30 mg once daily

40compared to placebo (61.6% and 69.5% vs 19.2%) among patients who achieved mucosal healing at
the end of induction.
Quality of life
Patients treated with upadacitinib demonstrated significantly greater and clinically meaningfulimprovement in health-related quality of life measured by the Inflammatory Bowel Disease
Questionnaire (IBDQ) total score compared to placebo. Improvements were seen in all 4 domainscores: systemic symptoms (including fatigue), social function, emotional function and bowel
symptoms (including abdominal pain and bowel urgency). Changes in IBDQ total score at week 8
from baseline with upadacitinib 45 mg once daily compared to placebo were 55.3 and 21.7 in UC-1
and 52.2 and 21.1 in UC-2, respectively. Changes in IBDQ total score at week 52 from baseline were49.2, 58.9 and 17.9 in patients treated with upadacitinib 15 mg, 30 mg once daily and placebo,
respectively.
Crohn’s disease
The efficacy and safety of upadacitinib was evaluated in three multicenter, double-blind,placebo-controlled Phase 3 studies: two induction studies, CD-1 (U-EXCEED) and CD-2 (U-EXCEL),
followed by a 52-week maintenance treatment and long-term extension study, CD-3 (U-ENDURE).
The co-primary endpoints were clinical remission and endoscopic response at week 12 for CD-1 andCD-2, and at week 52 for CD-3.
Enrolled patients were 18 to 75 years of age with moderately to severely active Crohn’s disease (CD),defined as an average daily very soft or liquid stool frequency (SF) ≥ 4 and/or average daily abdominal
pain score (APS) ≥ 2, and a centrally-reviewed Simple Endoscopic Score for CD (SES-CD) of ≥ 6, or≥ 4 for isolated ileal disease, excluding the narrowing component. Patients with symptomatic bowel
strictures were excluded from CD studies.
Induction studies (CD-1 and CD-2)
In CD-1 and CD-2, 1021 patients (495 and 526 patients, respectively) were randomised to upadacitinib
45 mg once daily or placebo for 12 weeks with a 2:1 treatment allocation ratio.
In CD-1, all patients had inadequate response or were intolerant to treatment with one or morebiologic therapies (prior biologic failure). Of these patients, 61% (301/495) had inadequate response
or were intolerant to two or more biologic therapies.
In CD-2, 45% (239/526) patients had an inadequate response or were intolerant to treatment with one
or more biologic therapies (prior biologic failure), and 55% (287/526) had an inadequate response orwere intolerant to treatment with conventional therapies but not to biologic therapy (without priorbiologic failure).
At baseline in CD-1 and CD-2, 34% and 36% of patients received corticosteroids, 7% and 3% of
patients received immunomodulators, and 15% and 25% of patients received aminosalicylates.
In both studies, patients receiving corticosteroids at baseline initiated a corticosteroid taper regimen
starting at week 4.
Both studies included a 12-week extended treatment period with upadacitinib 30 mg once daily forpatients who received upadacitinib 45 mg once daily and did not achieve clinical response per SF/APS(≥ 30% decrease in average daily very soft or liquid SF and/or ≥ 30% decrease in average daily APS
and neither greater than baseline) at week 12.

41

Clinical disease activity and symptoms
In CD-1 and CD-2, a significantly greater proportion of patients treated with upadacitinib 45 mg
achieved the co-primary endpoint of clinical remission at week 12 compared to placebo (Table 16).
Onset of efficacy was rapid and achieved as early as week 2 (Table 16).
In both studies, patients receiving upadacitinib 45 mg experienced significantly greater improvementfrom baseline in fatigue, as measured by FACIT-F score at week 12 compared to placebo.
Endoscopic assessment
In CD-1 and CD-2, a significantly greater proportion of patients treated with upadacitinib 45 mg
achieved the co-primary endpoint of endoscopic response at week 12 compared to placebo (Table 16).
In CD-1 and CD-2, a greater proportion of patients treated with upadacitinib 45 mg (14% and 19%,
respectively) compared to placebo (0% and 5%, respectively) achieved SES-CD 0-2.
Table 16 Proportion of patients meeting primary and additional efficacy endpoints in induction
studies CD-1 and CD-2
Study

CD-1
(U-EXCEED)
Treatment GroupUPA
Treatment
PBO
PBO
45 mg
Difference
N=171
N=176
N=324
(95% CI)
Co-Primary Endpoints at Week 12
Clinical remissiona
14%
40%
26%
22%
*
(19, 33)
Prior biologic failure
N=78
14%
Without prior biologic
N=98
failure29%
Endoscopic responseb
4%
35%
31%
13%
(25, 37)*
Prior biologic failure
N=78
9%Without prior biologic
N=98
failure16%
Additional Endpoints at Week 12
Clinical remission per
21%
39%
18%
29%
c
*
CDAI
(10, 26)
Clinical response
27%
51%
23%
37%
(CR-100)d(14, 31)*
Corticosteroid-free
N=60
N=108
30%
N=64
clinical remissiona,e7%
37%(19, 41)*
13%
Endoscopic remissionf
2%
19%
17%
7%
*
(12, 22)
Mucosal healingg
N=171
N= 322
17%
N=174
0%
17%
(13, 21)***
5%
Early Onset Endpoints
Clinical remission at
9%
32%
23%
15%
Week 4a(17, 30)*
CR-100 at Week 2d
12%
33%
21%
20%
(14, 28)*
Abbreviation: PBO = placebo, UPA = upadacitinib
42

CD-2(U-EXCEL)
UPA
Treatment
45 mg
Difference
N=350(95% CI)
51%
N=161
47%
N=189
54%
46%
N=161
38%
N=189
52%
49%
57%
N=126
44%
29%
N=349
25%
36%
32%

29%
(21, 36)*
33%(22, 44)26%(14, 37)
33%(26, 40)*
29%(19, 39)36%(25, 46)
21%(13, 29)*
20%(11, 28)*
33%(22, 44)*
22%(16, 28)*
20%(14, 25)***21%(14, 28)*12%(4, 19)***p < 0.001, adjusted treatment difference (95% CI)
p < 0.01, adjusted treatment difference (95% CI)***
nominal p < 0.001 UPA vs PBO comparison, adjusted treatment difference (95% CI)a
Average daily SF ≤ 2.8 and APS ≤ 1.0 and neither greater than baselineb
Decrease in SES-CD > 50% from baseline of the induction study (or for patients with an SES-CDof 4 at baseline of the induction study, at least a 2-point reduction from baseline of the induction
study)c
CDAI < 150dDecrease of at least 100 points in CDAI from baselineeDiscontinuation of steroid and achievement of clinical remission among patients on steroid atbaselinef
SES-CD ≤ 4 and at least a 2-point reduction versus baseline and no subscore > 1 in any individual
variableg
SES-CD ulcerated surface subscore of 0 in patients with SES-CD ulcerated surface subscore ≥ 1
at baseline**

Maintenance study (CD-3)
The efficacy analysis for CD-3 evaluated 502 patients who achieved clinical response per SF/APS
with the 12-week upadacitinib 45 mg once daily induction treatment. Patients were re-randomised toreceive a maintenance regimen of either upadacitinib 15 mg or 30 mg once daily or placebo for 52
weeks.
Clinical disease activity and symptoms
A significantly greater proportion of patients treated with upadacitinib 15 mg and 30 mg achieved theco-primary endpoint of clinical remission at week 52 compared to placebo (Figure 3, Table 17).

Percent Responders and 95%
Confidence Interval

Figure 3 Proportion of patients achieving clinical remission in maintenance study CD-3

Weeks
Placebo (N=165)

UPA 15 mg QD (N=169)

UPA 30 mg QD (N=168)

Patients receiving upadacitinib 30 mg experienced significantly greater improvement from baseline infatigue, as measured by FACIT-F score at week 52 compared to placebo.

43

Table 17 Proportion of patients meeting primary and additional efficacy endpoints at week 52 inmaintenance study CD-3
Treatment Group

PBO+
N=165

UPA
15 mg
N=169

UPA
30 mg
N=168

Treatment
Difference
15 mg vsPBO
(95% CI)

Treatment
Difference
30 mg vsPBO
(95% CI)

22%(14, 30)*
24%(14, 33)
12%(-9, 33)
21%(14, 28)*
19%(11, 27)
22%(3, 41)

32%(23, 40)*
34%(24, 44)26%(5, 47)
34%(26, 41)*
35%(26, 44)26%(7, 45)24%(15, 32)*
27%(18, 36)*
21%(13, 30)*
32%(20, 44)*14%(8, 21)*
10%(4, 16)***
10%(4, 16)**33%(24, 42)*36%(28, 45)*
30%(21, 39)*40%(28, 52)*
24%(16, 31)*21%(14, 27)***
18%(11, 25)*

Co-Primary Endpoints
Clinical remissiona
Prior biologic failure
Without prior biologic failure
Endoscopic responseb
Prior biologic failure
Without prior biologic failure

14%

36%

46%

N=126
9%
N=39
33%

N=124
32%
N=45
44%

N=127
43%
N=41
59%

7%

28%

40%

N=126
N=124
N=127
4%
23%
39%
N=39
N=45
N=41
18%
40%
44%
Additional Endpoints

Clinical remission per CDAIc

15%

37%

48%

Clinical response (CR-100)d

15%

41%

51%

14%

35%

45%

N=101
20%

N=105
50%

N=105
60%

5%

19%

29%

Mucosal healingh

N=164
4%

N=167
13%

N=168
24%

Deep remission a,i

4%

14%

23%

Corticosteroid-free clinicalremissiona,eMaintenance of clinicalremission a,f
Endoscopic remissiong

Abbreviation: PBO = placebo, UPA = upadacitinib+
The placebo group consisted of patients who achieved clinical response per SF/APS withupadacitinib 45 mg at the end of the induction study and were randomised to receive placebo at thestart of maintenance therapy*
p < 0.001, adjusted treatment difference (95% CI)**
p < 0.01, adjusted treatment difference (95% CI)***
nominal p < 0.001 UPA vs PBO comparison, adjusted treatment difference (95% CI)a
Average daily SF ≤ 2.8 and APS ≤ 1.0 and neither greater than baselineb
Decrease in SES-CD > 50% from baseline of the induction study (or for patients with an SES-CDof 4 at baseline of the induction study, at least a 2-point reduction from baseline of the induction
study)c
CDAI < 150dReduction of CDAI ≥ 100 points from baselineeCorticosteroid-free for 90 days prior to week 52 and achievement of clinical remission. Among thesubset of patients who were on corticosteroids at induction baseline, 38% (N=63) in upadacitinib
44

15 mg group, 38% (N=63) in upadacitinib 30 mg group, and 5% (N=61) in placebo were
corticosteroid-free for 90 days prior to week 52 and in clinical remissionfDefined as achievement of clinical remission at Week 52 in patients who achieved clinicalremission at the entry of the maintenance studyg
SES-CD ≤ 4 and at least a 2-point reduction versus baseline and no subscore >1 in any individual
variableh
SES-CD ulcerated surface subscore of 0 in patients with SES-CD ulcerated surface subscore ≥ 1 atbaselinei
Clinical remission and endoscopic remission
Patients who were not in clinical response per SF/APS to upadacitinib induction at week 12 in CD-1
and CD-2 (122 patients) received upadacitinib 30 mg once daily for an additional 12 weeks. Of thesepatients, 53% achieved clinical response at week 24. Of the patients who responded to the extended
treatment period and continued to receive maintenance treatment with upadacitinib 30 mg, 25%
achieved clinical remission and 22% achieved endoscopic response at week 52.
Endoscopic assessment
In CD-3, a significantly greater proportion of patients treated with upadacitinib 15 mg and 30 mg
achieved the co-primary endpoint of endoscopic response at week 52 compared to placebo (Table 17).
In addition to the endoscopic endpoints described in Table 17, a greater proportion of patients treatedwith upadacitinib 15 mg and 30 mg (11% and 21%, respectively) compared to placebo (3%) achieved
SES-CD 0-2 at week 52. Corticosteroid-free endoscopic remission among patients on steroid atbaseline was achieved in a greater proportion of patients treated with upadacitinib 15 mg and 30 mg(17% and 25%, respectively) compared to placebo (3%) at week 52.
Resolution of extra-intestinal manifestations
Resolution of extra-intestinal manifestations was observed in a greater proportion of patients treatedwith upadacitinib 15 mg (25%) and a significantly greater proportion of patients treated withupadacitinib 30 mg (36%) compared to placebo (15%) at week 52.
Rescue treatment
In CD-3, patients who demonstrated inadequate response or lost response during maintenance were
eligible to receive rescue treatment with upadacitinib 30 mg. Of the patients who were randomised toupadacitinib 15 mg group and received rescue treatment of upadacitinib 30 mg for at least 12 weeks,
84% (76/90) achieved clinical response per SF/APS and 48% (43/90) achieved clinical remission 12
weeks after initiating rescue.
Health-related quality of life outcomes
Patients treated with upadacitinib achieved greater improvement in health-related quality of life
(HRQOL) measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) total score comparedto placebo. Improvements were seen in all 4 domain scores: systemic symptoms (including fatigue)
and bowel symptoms (including abdominal pain and bowel urgency), as well as social and emotional
functioning. Changes from baseline in IBDQ total score at week 12 with upadacitinib 45 mg once
daily compared to placebo were 46.0 and 21.6 in CD-1 and 46.3 and 24.4 in CD-2, respectively.
Changes in IBDQ total score at week 52 from baseline were 59.3, 64.5 and 46.4 in patients treatedwith upadacitinib 15 mg, 30 mg once daily and placebo, respectively.
Paediatric population
A total of 344 adolescents aged 12 to 17 years with moderate to severe atopic dermatitis wererandomised across the three Phase 3 studies to receive either 15 mg (N=114) or 30 mg (N=114)
upadacitinib or matching placebo (N=116), in monotherapy or combination with topicalcorticosteroids. Efficacy was consistent between the adolescents and adults. The safety profile in45

adolescents was generally similar to that in adults, with dose-dependent increases in the rate of someadverse events, including neutropaenia and herpes zoster. At both doses, the rate of neutropaenia wasslightly increased in adolescents compared to adults. The rate of herpes zoster in adolescents at the
30 mg dose was comparable to that in adults. The safety and efficacy of the 30 mg dose in adolescentsare still being investigated.
Table 18 Efficacy results of upadacitinib for adolescents at week 16
StudyTreatment GroupMEASURE UP 1
PBO
UPA
15 mg

Number ofadolescent subjects
40
randomised% responders (95% CI)
vIGA-AD 0/1 a,b
8(0,16)EASI 75a8(0,17)
Worst Pruritus
15cNRS(4,27)(≥ 4-point
improvement)

MEASURE UP 2
PBO
UPA
15 mg

PBO +
TCS

AD UP
UPA
15 mg + TCS

42

36

33

40

39

38
(23,53)71(58,85)45(30,60)3(0,8)
14(3,25)
3(0,8)

42(26,59)67(51,83)
33(16,50)8(0,16)
30(16,44)13(2,24)

31(16,45)
56(41,72)
42(26,58)Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo
Subjects with rescue medication or with missing data were counted as non-responders.
aBased on number of subjects randomisedbResponder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with areduction of ≥ 2 points on a 0-4 ordinal scale.
cResults shown in subset of patients eligible for assessment (patients with Worst Pruritus
NRS ≥ 4 at baseline).
The European Medicines Agency has deferred the obligation to submit the results of studies with
RINVOQ in one or more subsets of the paediatric population in chronic idiopathic arthritis (including
rheumatoid arthritis, psoriatic arthritis, spondyloarthritis and juvenile idiopathic arthritis) atopic
dermatitis, ulcerative colitis, and Crohn’s disease (see section 4.2 for information on paediatric use).
5.2

Pharmacokinetic properties

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 dailyadministrations.
Absorption
Following oral administration of upadacitinib prolonged-release formulation, upadacitinib is absorbedwith 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 C max 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 andblood cellular components, as indicated by the blood to plasma ratio of 1.0.

46

Metabolism
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 humanradiolabeled 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 AUC was 18%, 33%, and 44% higher in subjects with mild (estimated glomerular
filtration rate 60 to 89 ml/min/1.73 m2), moderate (estimated glomerular filtration rate 30 to
59 ml/min/1.73 m2), and severe (estimated glomerular filtration rate 15 to 29 ml/min/1.73 m2) renal
impairment, respectively, compared to subjects with normal renal function. Upadacitinib Cmax was
similar in subjects with normal and impaired renal function. Mild or moderate renal impairment has noclinically relevant effect on upadacitinib exposure (see section 4.2).
Hepatic impairment
Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment has no clinically relevant
effect on upadacitinib exposure. Upadacitinib AUC was 28% and 24% higher in subjects with mildand moderate hepatic impairment, respectively, compared to subjects with normal liver function.
Upadacitinib Cmax was unchanged in subjects with mild hepatic impairment and 43% higher insubjects with moderate hepatic impairment compared to subjects with normal liver function.
Upadacitinib was not studied in patients with severe (Child-Pugh C) hepatic impairment.
Paediatric population
The pharmacokinetics of upadacitinib have not yet been evaluated in paediatric patients withrheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, ulcerative colitis, and Crohn’s disease(see section 4.2).
Upadacitinib pharmacokinetics and steady-state concentrations are similar for adults and adolescents
12 to 17 years of age with atopic dermatitis. The posology in adolescent patients 30 kg to < 40 kg wasdetermined using population pharmacokinetic modelling and simulation.
The pharmacokinetics of upadacitinib in paediatric patients (< 12 years of age) with atopic dermatitis
have not been established.
Intrinsic factors
Age, sex, body weight, race, and ethnicity did not have a clinically meaningful effect on upadacitinib
exposure. Upadacitinib pharmacokinetics are consistent between rheumatoid arthritis, psoriatic
arthritis, axial spondyloarthritis, atopic dermatitis, ulcerative colitis, and Crohn’s disease patients.

47

5.3

Preclinical safety dataNon-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology.
Upadacitinib, at exposures (based on AUC) approximately 4 and 10 times the clinical dose of 15 mg, 2
and 5 times the clinical dose of 30 mg, and 1.7 and 4 times the clinical dose of 45 mg in male andfemale Sprague-Dawley rats, respectively, was not carcinogenic in a 2-year carcinogenicity study inSprague-Dawley rats. Upadacitinib was not carcinogenic in a 26-week carcinogenicity study in
CByB6F1-Tg(HRAS)2Jic transgenic mice.
Upadacitinib was not mutagenic or genotoxic based on the results of in vitro and in vivo tests for genemutations and chromosomal aberrations.
Upadacitinib had no effect on fertility in male or female rats at exposures up to approximately 17 and34 times the maximum recommended human dose (MRHD) of 45 mg in males and females,
respectively, on an AUC basis in a fertility and early embryonic development study. Dose-related
increases in foetal resorptions associated with post-implantation losses in this fertility study in rats
were attributed to the developmental/teratogenic effects of upadacitinib. No adverse effects wereobserved at exposures below clinical exposure (based on AUC). Post-implantation losses wereobserved at exposures 9 times the clinical exposure at the MRHD of 45 mg (based on AUC).
In animal embryo-foetal development studies, upadacitinib was teratogenic in both rats and rabbits.
Upadacitinib resulted in increases in skeletal malformations in rats at 1.6, 0.8, and 0.6 times theclinical exposure (AUC-based) at the 15, 30, and 45 mg (MRHD) doses, respectively. In rabbits anincreased incidence of cardiovascular malformations was observed at 15, 7.6, and 6 times the clinicalexposure at the 15, 30, and 45 mg doses (AUC-based), respectively.
Following administration of upadacitinib to lactating rats, the concentrations of upadacitinib in milk
over time generally paralleled those in plasma, with approximately 30-fold higher exposure in milk
relative to maternal plasma. Approximately 97% of upadacitinib-related material in milk was theparent molecule, upadacitinib.
6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet contents
Microcrystalline cellulose
Hypromellose
MannitolTartaric acid
Silica, colloidal anhydrous
Magnesium stearate
Film coating
Poly(vinyl alcohol)
Macrogol
Talc
Titanium dioxide (E171)
Iron oxide black (E172) (15 mg strength only)
Iron oxide red (E172)
Iron oxide yellow (E172) (45 mg strength only)
48

6.2

Incompatibilities

Not applicable.
6.3

Shelf life

RINVOQ 15 mg prolonged-release tablets
Prolonged-release tablets in blisters: 2 years
Prolonged-release tablets in bottles: 3 years
RINVOQ 30 mg prolonged-release tablets
Prolonged-release tablets in blisters: 2 years
Prolonged-release tablets in bottles: 3 years
RINVOQ 45 mg prolonged-release tablets
2 years
6.4

Special precautions for storage

This medicinal product does not require any special temperature storage conditions.
Store in the original blister or bottle in order to protect from moisture. Keep the bottle tightly closed.
6.5

Nature and contents of container

RINVOQ 15 mg prolonged-release tablets
Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packs
containing 28 or 98 prolonged-release tablets, or multipacks containing 84 (3 packs of 28) prolongedrelease tablets.
HDPE bottles with desiccant and polypropylene cap in carton containing 30 prolonged-release tablets.
Pack size: 1 bottle (30 prolonged-release tablets) or 3 bottles (90 prolonged-release tablets).
Not all pack sizes may be marketed.
RINVOQ 30 mg prolonged-release tablets
Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packs
containing 28 or 98 prolonged-release tablets.
HDPE bottles with desiccant and polypropylene cap in carton containing 30 prolonged-release tablets.
Pack size: 1 bottle (30 prolonged-release tablets) or 3 bottles (90 prolonged-release tablets).
Not all pack sizes may be marketed.
RINVOQ 45 mg prolonged-release tablets
Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packs
containing 28 prolonged-release tablets.
HDPE bottles with desiccant and polypropylene cap in carton containing 28 prolonged-release tablets.

49Not all pack sizes may be marketed.
6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.

MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
8.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/001
EU/1/19/1404/002
EU/1/19/1404/003
EU/1/19/1404/004
EU/1/19/1404/005
EU/1/19/1404/006
EU/1/19/1404/007
EU/1/19/1404/008
EU/1/19/1404/009
EU/1/19/1404/010
EU/1/19/1404/011
9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 December 201910.

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.

50

ANNEX IIA.

MANUFACTURER(S) RESPONSIBLE FOR BATCH
RELEASEB.

CONDITIONS OR RESTRICTIONS REGARDING SUPPLYAND USEC.

OTHER CONDITIONS AND REQUIREMENTS OF THE
MARKETING AUTHORISATION

D.

CONDITIONS OR RESTRICTIONS WITH REGARD TO
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT

51

A.

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers responsible for batch release
AbbVie S.r.l.
148, Pontina Km 52 snc
04011
Campoverde di Aprilia (LT)
ITALY
And
AbbVie Logistics B.V
Zuiderzeelaan 538017 JV Zwolle
NETHERLANDS
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B.

CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of ProductCharacteristics, section 4.2).
C.

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION•

Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list ofUnion reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
and any subsequent updates published on the European medicines web-portal.
D.

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT•Risk management plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in
the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed
subsequent updates of the RMP.
An updated RMP should be submitted:• At the request of the European Medicines Agency;• Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk
profile or as the result of an important (pharmacovigilance or risk minimisation)
milestone being reached.
•
Additional risk minimisation measures
Prior to launch of RINVOQ in each Member State the Marketing Authorisation Holder (MAH)must agree about the content and format of the educational programme, including52

communication media, distribution modalities, and any other aspects of the programme, with
the National Competent Authority.
The objective of the programme is to increase awareness of HCPs and patients on the risks ofserious and opportunistic infections including TB, herpes zoster, foetal malformation(pregnancy risk), MACE, VTE, and malignancy and how to manage these risks.
The MAH shall ensure that in each Member State where RINVOQ is marketed, all healthcare
professionals and patients/carers who are expected to prescribe, dispense or use RINVOQ haveaccess to/are provided with the following educational package:
The physician educational material should contain:• The Summary of Product Characteristics• Guide for healthcare professionals• Patient card
The Guide for healthcare professionals shall contain the following key elements:• General introductory language that the HCP measure contains important information toassist the discussion with patients when prescribing upadacitinib. The brochure also
informs on steps which can be taken to reduce a patient's risk for key safety aspects of
upadacitinib.
• Indication and posology statements provided to reinforce in whom upadacitinib should be
used• Use in patients 65 years of age and older
o Language to reinforce risks in these patients and use of the 15 mg dose
• Language for HCPs to inform patients of the importance of the patient card
• Risk of serious and opportunistic infections including TB
o Language on the risk of infections during treatment with upadacitinibo Language on increased risk of serious infections in patients 65 years of age andolder
o Details on how to reduce the risk of infection with specific clinical measures(what laboratory parameters should be used to initiate upadacitinib, screening
for tuberculosis (TB), and getting patients immunised as per local guidelines,
and interruption of upadacitinib if an infection develops)o Language on contraindication in patients with active TB and on considerationof anti-TB therapy in patients with latent TB
o Language on avoidance of live vaccines (i.e., Zostavax) prior to and during
upadacitinib treatment
o Details to advise patients on signs/symptoms of infection to be aware of, so thatpatients can seek medical attention quickly.
• Risk of herpes zoster
o Language on the risk of herpes zoster during treatment with upadacitinibo Details to advise patients on signs/symptoms of infection to be aware of, so thatpatients can seek medical attention quickly.
• Risk of foetal malformationo Language on teratogenicity of upadacitinib in animals
o Details on how to reduce the risk of exposure during pregnancy for female
patients of childbearing potential based on the following: upadacitinib iscontraindicated during pregnancy, female patients of childbearing potential
should be advised to use effective contraception both during treatment and for 4
weeks after the final dose of upadacitinib treatment, and to advise patients to
inform their HCP immediately if they think they could be pregnant or if
pregnancy is confirmed.

53

• Risk of MACE
o In patients at high risk for MACE upadacitinib should only be used if nosuitable treatment alternatives are available, with examples of who may be athigh risk.
o Language on the risk of hyperlipidaemia during upadacitinib therapy
o Details on monitoring of lipid levels and management of elevated lipid levels
per clinical guidelines• Risk of VTE
o Examples of the risk factors which may put a patient at higher risk for venous
thromboembolic event (VTE) and in whom caution is needed when using
upadacitinib.
o Use of caution in patients at high risk during treatment with upadacitinibo Language that patients should be periodically reevaluated for changes in VTE
risko Language on need for discontinuation of upadacitinib, evaluation, andappropriate treatment for VTE if clinical features of deep venous thrombosis or
pulmonary embolism develop• Risk of Malignancy
o In patients at high risk for malignancy upadacitinib should only be used if nosuitable treatment alternatives are available, with examples of who may be athigh risk.
o Reminder about the need for periodic skin examination for patients.
• Risk of gastrointestinal perforationo Upadacitinib should be used with caution in patients at risk for gastrointestinal
perforation with examples of those who may be at risk.
o Reminder that patients presenting with new onset abdominal signs and symptoms
should be evaluated promptly for early identification of diverticulitis or
gastrointestinal perforation.
Information for upadacitinib use in moderate to severe AD
The 30 mg upadacitinib dose in atopic dermatitis• Language on dose-dependent increase in serious infections and herpes zoster
with upadacitinib.
• Language on dose-dependent increase in NMSC and malignancy• Language on dose-dependent increase in plasma lipids with upadacitinib.
• Language that the 30 mg dose is not recommended in certain populations(patients with severe renal impairment and patients taking strong CYP3A4
inhibitors).
• Language to reinforce that the lowest effective dose of upadacitinib should be used fortreatment.
Upadacitinib use in adolescents 12 years and older• Reminder that live, attenuated vaccines (ie. varicella, MMR, BCG) which
depending on local guidelines may be considered in adolescents. Language notto administer these vaccines immediately prior to or during upadacitinib
treatment.
• Language to remind adolescents of the potential pregnancy risks and on theappropriate use of effective contraception.
• Language that if their adolescent patient has not experienced menarche, toinform their adolescent patient or caregiver to let them know when they do.

54

Information for upadacitinib use in moderate to severe ulcerative colitis (UC) or Crohn’s disease(CD)• Reminder to review induction and maintenance dosing in product labeling.
• Language on dose-dependent increase in serious infections and herpes zoster
with upadacitinib• Language on dose-dependent increase in NMSC and malignancy• Reminder about induction and maintenance dose in certain populations(patients taking strong CYP3A4 inhibitors and severe renal impairment).
• Language to reinforce that the lowest effective dose of upadacitinib should be
used for maintenance treatment
Instructions on where to report AEs will be included.
Instructions for how to access digital HCP information will be included, if applicable.
The patient information pack should contain:• Patient information leaflet• A patient card
• The patient card shall contain the following key messages:o Contact details of the upadacitinib prescribero Language that the patient card should be carried by the patient at any time and toshare it with HCPs involved in their care (i.e., non-upadacitinib prescribers,
emergency room HCPs, etc.)
o Description of signs/symptoms of infections the patient needs to be aware of, sothat they can seek attention from their HCP:
• Language to advise patients and their HCPs about the risk of live vaccinations
when given during upadacitinib therapy. Examples of live vaccines areprovided.
• Language to advise patients to tell their HCP if they have history or have beenin contact with TB.
o Description of targeted risks for awareness by the patient and for HCPs involved intheir care including:• Risk of heart disease:o Describe signs/symptoms of heart disease that the patient needs to beaware of, so that they can seek attention from their HCPo A reminder to use contraception, that upadacitinib is contraindicated during
pregnancy, and to notify their HCPs if they become pregnant while taking
upadacitinibo Description of signs/symptoms of deep venous thrombosis or pulmonary embolism
which the patient needs to be aware of, so that they can seek attention from an HCP
o Reminder of the risk of cancer. Regarding skin cancer reminder to let their doctor
know if they notice any new growth on the skin.
o Risk of a hole in the bowel – description of signs/symptoms which the patient needs to beaware of, so that they can seek attention from an HCP

55

ANNEX III
LABELLING AND PACKAGE LEAFLET

56

A. LABELLING

57

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Blister Carton (Individual carton)

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.

58

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/001
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 15 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

59

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton for 84 tablet multipack (with Blue Box)

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

Multipack: 84 (3 packs of 28) prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.

60

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/003
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 15 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

61

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Intermediate carton of 84 tablet multipack (without Blue Box)

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets.
Component of a multipack, can’t be sold separately.
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATE

EXP

62

9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/003
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 15 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

63

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton of 98 tablets

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

98 prolonged-release tablets.
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.

64

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/005
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 15 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

65

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Inner carton of 49 tablets (for the 98 pack)1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

49 prolonged-release tablets.
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.

66

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/005
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 15 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA67MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

NAME OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)
3.

EXPIRY DATEEXP
4.

BATCH NUMBER

Lot
5.

OTHER

Mon. Tue. Wed. Thu. Fri. Sat. Sun.

68

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Bottle Carton (30 and 90 pack)1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets
90 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
Do not swallow the desiccant.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATE

EXP

69

9.

SPECIAL STORAGE CONDITIONSStore in the original bottle and keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/002
EU/1/19/1404/004
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 15 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

70

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
Bottle Label

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 15 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg upadacitinib
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
Do not swallow the desiccant.
Important to open
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original bottle and keep the bottle tightly closed in order to protect from moisture.
71

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)
12.

MARKETING AUTHORISATION NUMBER(S)13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

17.

UNIQUE IDENTIFIER – 2D BARCODE

18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

72

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Blister Carton (Individual carton)

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 30 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.

73

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/006
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 30 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

74

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton of 98 tablets

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 30 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

98 prolonged-release tablets.
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.

75

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/009
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 30 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

76

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Inner carton of 49 tablets (for the 98 pack)1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 30 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

49 prolonged-release tablets.
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.

77

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/009
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 30 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA78MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 30 mg prolonged-release tablets
upadacitinib
2.

NAME OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)
3.

EXPIRY DATEEXP
4.

BATCH NUMBER

Lot
5.

OTHER

Mon. Tue. Wed. Thu. Fri. Sat. Sun.

79

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Bottle Carton (30 and 90 pack)1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 30 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets
90 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
Do not swallow the desiccant.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATE

EXP

80

9.

SPECIAL STORAGE CONDITIONSStore in the original bottle and keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/007
EU/1/19/1404/008
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 30 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

81

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
Bottle Label

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 30 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg upadacitinib
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
Do not swallow the desiccant.
Important to open
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original bottle and keep the bottle tightly closed in order to protect from moisture.
82

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)
12.

MARKETING AUTHORISATION NUMBER(S)13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

17.

UNIQUE IDENTIFIER – 2D BARCODE

18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

83

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Blister/Bottle Carton

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 45 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 45 mg upadacitinib.
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
Do not swallow the desiccant.
QR code to be included
For more information and support on taking RINVOQ go to www.rinvoq.eu
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original blister in order to protect from moisture.
84

Store in the original bottle and keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
12.

MARKETING AUTHORISATION NUMBER(S)EU/1/19/1404/010
EU/1/19/1404/011
13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

rinvoq 45 mg
17.

UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.
18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

85

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 45 mg prolonged-release tablets
upadacitinib
2.

NAME OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)
3.

EXPIRY DATEEXP
4.

BATCH NUMBER

Lot
5.

OTHER

Mon. Tue. Wed. Thu. Fri. Sat. Sun.

86

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
Bottle Label

1.

NAME OF THE MEDICINAL PRODUCTRINVOQ 45 mg prolonged-release tablets
upadacitinib
2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 45 mg upadacitinib
3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

28 prolonged-release tablets
5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Do not chew, crush or break the tablet. Swallow whole.
Do not swallow the desiccant.
Important to open
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.

OTHER SPECIAL WARNING(S), IF NECESSARY8.

EXPIRY DATEEXP
9.

SPECIAL STORAGE CONDITIONSStore in the original bottle and keep the bottle tightly closed in order to protect from moisture.
87

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AbbVie (as logo)
12.

MARKETING AUTHORISATION NUMBER(S)13.

BATCH NUMBER

Lot
14.

GENERAL CLASSIFICATION FOR SUPPLY

15.

INSTRUCTIONS ON USE

16.

INFORMATION IN BRAILLE

17.

UNIQUE IDENTIFIER – 2D BARCODE

18.

UNIQUE IDENTIFIER - HUMAN READABLE DATA

88

B. PACKAGE LEAFLET89

Package leaflet: Information for the patient
RINVOQ 15 mg prolonged-release tablets
RINVOQ 30 mg prolonged-release tablets
RINVOQ 45 mg prolonged-release tablets
upadacitinib
This medicine is subject to additional monitoring. This will allow quick identification of newsafety information. You can help by reporting any side effects you may get. See the end of section 4for how to report side effects.
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible
side effects not listed in this leaflet. See section 4.
What is in this leaflet
1.
2.
3.
4.
5.
6.

What RINVOQ is and what it is used for
What you need to know before you take RINVOQ
How to take RINVOQ
Possible side effects
How to store RINVOQ
Contents of the pack and other information

1.

What RINVOQ is and what it is used for

RINVOQ contains the active substance upadacitinib. It belongs to a group of medicines called Janus
kinase inhibitors. By reducing the activity of an enzyme called ‘Janus kinase’ in the body, RINVOQ
lowers inflammation in the following diseases:
•
•
•
•
•
•

Rheumatoid arthritis
Psoriatic arthritis
Axial spondyloarthritis• Non-radiographic axial spondyloarthritis• Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)
Atopic dermatitis
Ulcerative colitis
Crohn’s disease

Rheumatoid arthritis
RINVOQ is used to treat adults with rheumatoid arthritis. Rheumatoid arthritis is a disease that causes
inflamed joints. If you have moderate to severe active rheumatoid arthritis, you may first be given
other medicines, one of which will usually be methotrexate. If these medicines do not work wellenough, you will be given RINVOQ either alone or in combination with methotrexate to treat yourrheumatoid arthritis.
RINVOQ can help to reduce pain, stiffness and swelling in your joints, reduce tiredness and it canslow down damage to the bone and cartilage in your joints. These effects can ease your normal daily
activities and so improve your quality of life.
90

Psoriatic arthritis
RINVOQ is used to treat adults with psoriatic arthritis. Psoriatic arthritis is a disease that causes
inflamed joints and psoriasis. If you have active psoriatic arthritis, you may first be given othermedicines. If these medicines do not work well enough, you will be given RINVOQ either alone or in
combination with methotrexate to treat your psoriatic arthritis.
RINVOQ can help to reduce pain, stiffness, and swelling in and around your joints, pain and stiffness
in your spine, psoriatic skin rash, and tiredness, and it can slow down damage to the bone and cartilage
in your joints. These effects can ease your normal daily activities and so improve your quality of life.
Axial spondyloarthritis (non-radiographic axial spondyloarthritis and ankylosing spondylitis)
RINVOQ is used to treat adults with axial spondyloarthritis. Axial spondyloarthritis is a disease thatprimarily causes inflammation in the spine. If you have active axial spondyloarthritis, you may first be
given other medicines. If these medicines do not work well enough, you will be given RINVOQ totreat your axial spondyloarthritis.
RINVOQ can help to reduce back pain, stiffness, and inflammation in your spine. These effects canease your normal daily activities and so improve your quality of life.
Atopic dermatitis
RINVOQ is used to treat adults and adolescents 12 years and older with moderate to severe atopic
dermatitis, also known as atopic eczema. RINVOQ may be used with eczema medicines that you
apply to the skin or it may be used on its own.
Taking RINVOQ can improve the condition of your skin, and reduce itching and flares. RINVOQ canhelp improve symptoms of pain, anxiety and depression that people with atopic dermatitis may have.
RINVOQ can also help improve your sleep disturbance and overall quality of life.
Ulcerative colitis
Ulcerative colitis is an inflammatory disease of the large bowel. RINVOQ is used to treat adults withulcerative colitis who did not respond well enough or did not tolerate previous therapy.
RINVOQ can help to reduce the signs and symptoms of the disease including bloody stools,
abdominal pain and the need to rush to and the number of times you go to the toilet. These effects canenable your normal daily activities and reduce fatigue.
Crohn’s disease
Crohn’s disease is an inflammatory disease that may involve any part of the digestive tract, but mostcommonly affects the bowel. RINVOQ is used to treat adults with Crohn’s disease who did not
respond well enough or did not tolerate previous therapy.
RINVOQ can help to reduce the signs and symptoms of the disease including the need to rush to andthe number of times you go to the toilet, abdominal pain, and the inflammation of your intestinal
lining. These effects can enable your normal daily activities and reduce fatigue.
2.

What you need to know before you take RINVOQ

Do not take RINVOQ•
if you are allergic to upadacitinib or any of the other ingredients of this medicine (listed in
section 6)•
if you have a severe infection (such as pneumonia or bacterial skin infection)•
if you have active tuberculosis (TB)•
if you have severe liver problems•
if you are pregnant (see section Pregnancy, breast-feeding and contraception)
91

Warnings and precautions
Talk to your doctor or pharmacist before and during treatment with RINVOQ if:•
you have an infection or if you often get infections. Tell your doctor if you get symptoms suchas fever, wounds, feeling more tired than usual or dental problems as these can be signs ofinfection. RINVOQ can reduce your body’s ability to fight infections and may make an existing
infection worse or increase the chance of you getting a new infection. If you have diabetes orare 65 years of age or older you may have an increased chance of getting infections•
you have had tuberculosis or have been in close contact with someone with tuberculosis. Your
doctor will test you for tuberculosis before starting RINVOQ and may retest during treatment•
you have had a herpes zoster infection (shingles), because RINVOQ may allow it to come back.
Tell your doctor if you get a painful skin rash with blisters as these can be signs of shingles•
you have ever had hepatitis B or C•
you have recently had or plan to have a vaccination (immunisation) - this is because live
vaccines are not recommended while using RINVOQ•
you have or had in the past cancer, smoke or have smoked in the past, because your doctor will
discuss with you if RINVOQ is appropriate for you•
non-melanoma skin cancer has been observed in patients taking RINVOQ. Your doctor may
recommend that you have regular skin examinations while taking RINVOQ. If new skin lesions
appear during or after therapy or if existing lesions change appearance, tell your doctor.
•
have, or have had, heart problems, because your doctor will discuss with you if RINVOQ isappropriate for you•
your liver does not work as well as it should•
you have previously had blood clots in the veins of your legs (deep vein thrombosis) or lungs(pulmonary embolism) or have an increased risk for developing this (for example: if you had
recent major surgery, if you use hormonal contraceptives\hormonal replacement therapy, if ablood clotting disorder is identified in you or your close relatives). Your doctor will discuss withyou if RINVOQ is appropriate for you. Tell your doctor if you get sudden shortness of breath ordifficulty breathing, chest pain or pain in upper back, swelling of the leg or arm, leg pain or
tenderness, or redness or discolouration in the leg or arm as these can be signs of blood clots inthe veins•
you have kidney problems•
you have unexplained stomach (abdominal) pain, have or have had diverticulitis (painful
inflammation of small pockets in the lining of your intestine) or ulcers in your stomach or
intestines, or are taking non-steroidal anti-inflammatory medicines.
If you notice any of the following serious side effects, tell a doctor straight away:• symptoms such as a rash (hives), trouble breathing, or swelling of your lips, tongue, or throat, you
may be having an allergic reaction. Some people taking RINVOQ had serious allergic reactions. If
you have any of these symptoms during treatment with RINVOQ, stop taking RINVOQ and get
emergency medical help straight away
• severe stomach pain especially accompanied by fever, nausea, and vomiting.
Blood tests
You will need blood tests before you start taking RINVOQ, or while you are taking it. This is to checkfor a low red blood cell count (anaemia), low white blood cell count (neutropaenia or lymphopaenia),
high blood fat (cholesterol) or high levels of liver enzymes. The tests are to check that treatment with
RINVOQ is not causing problems.
Elderly
There is a higher rate of infection in patients aged 65 years of age and older. Tell your doctor as soon
as you notice any signs or symptoms of an infection.
Patients 65 years of age and older may be at increased risk of infections, heart problems including
heart attack, and some types of cancer. Your doctor will discuss with you if RINVOQ is appropriate
for you.

92

Children and adolescents
RINVOQ is not recommended for use in children under 12 years of age or adolescents weighing lessthan 30 kg with atopic dermatitis. This is because it has not been studied in these patients.
RINVOQ is not recommended for use in children and adolescents under 18 years of age withrheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (non-radiographic axial
spondyloarthritis and ankylosing spondylitis), ulcerative colitis, or Crohn’s disease. This is because it
has not been studied in this age group.
Other medicines and RINVOQ
Tell your doctor or pharmacist if you are taking, have recently taken or might take any othermedicines. This is because some medicines may reduce how well RINVOQ works or may increase therisk of getting side effects. It is very important to talk to your doctor or pharmacist if you are taking
any of the following:•
medicines to treat fungal infections (such as itraconazole, posaconazole or voriconazole)•
medicines to treat bacterial infections (such as clarithromycin)•
medicines to treat Cushing’s syndrome (such as ketoconazole)•
medicines to treat tuberculosis (such as rifampicin)•
medicines to treat seizures or fits (such as phenytoin)•
medicines that affect your immune system (such as azathioprine, 6-mercaptopurine, ciclosporin
and tacrolimus)•
medicines that may increase your risk of gastrointestinal perforation or diverticulitis such as
non-steroidal anti-inflammatory medicines (usually used to treat painful and/or inflammatory
conditions of muscle or joints), and/or opioids (used to treat severe pain), and/or corticosteroids(usually used to treat inflammatory conditions).
•
medicines to treat diabetes or if you have diabetes. Your doctor may decide if you need lessanti-diabetic medicine while taking upadacitinib.
If any of the above apply to you or you are not sure, talk to your doctor or pharmacist before taking
RINVOQ.
Pregnancy, breast-feeding and contraception
Pregnancy
RINVOQ must not be used during pregnancy.
Breast-feeding
If you are breast-feeding or are planning to breast-feed, talk to your doctor before taking this medicine.
You should not use RINVOQ while breast-feeding as it is not known if this medicine passes into
breast milk. You and your doctor should decide if you will breast-feed or use RINVOQ. You should
not do both.
Contraception
If you are a woman of child-bearing potential, you must use effective contraception to avoid becoming
pregnant while taking RINVOQ and for at least 4 weeks after your last dose of RINVOQ. If you
become pregnant during this time, you must talk to your doctor straight away.
If your child has her first menstrual period while taking RINVOQ, you should inform the doctor.
Driving and using machines
Do not drive or use machines if you experience dizziness or a spinning sensation (vertigo) when taking
RINVOQ until they resolve.

93

3.

How to take RINVOQ

Always take this medicine exactly as your doctor or pharmacist has told you. Check with yourdoctor or pharmacist if you are not sure.
How much to takeIf you have rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis (non-radiographic axial
spondyloarthritis and ankylosing spondylitis)
The recommended dose is one 15 mg tablet once a day.
If you have atopic dermatitis
Adults:
The recommended dose is 15 mg or 30 mg as prescribed by your doctor, as one tablet once a day.
Your doctor may increase or decrease your dose depending on how well the medicine is working.
Elderly:
If you are 65 years of age or older, the recommended dose is 15 mg once a day.
Adolescents (from 12 to 17 years of age) weighing at least 30 kg:
The recommended dose is one 15 mg tablet once a day.
If you have ulcerative colitis
The recommended dose is one 45 mg tablet once a day for 8 weeks. Your doctor may decide to extend
the initial 45 mg dose for another 8 weeks (for 16 weeks total). This will be followed by one 15 mg orone 30 mg tablet once a day for your long-term treatment. Your doctor may increase or decrease yourdose depending on how you respond to the medicine.
Elderly:
If you are 65 years of age or older, the recommended dose is 15 mg once a day for your long-term
treatment.
Your doctor may reduce your dose if you have kidney problems, or you are prescribed certain othermedicines.
If you have Crohn’s disease
The recommended dose is one 45 mg tablet once a day for 12 weeks. This will be followed by one
15 mg or one 30 mg tablet once a day for your long-term treatment. Your doctor may increase or
decrease your dose depending on how you respond to the medicine.
Elderly:
If you are 65 years of age or older, the recommended dose is 15 mg once a day for your long-term
treatment.
Your doctor may reduce your dose if you have kidney problems, or you are prescribed certain othermedicines.

94How to take
•
•
•
•
•

Swallow the tablet whole with water. Do not split, crush, chew or break the tablet before
swallowing as it may change how much medicine gets into your body.
To help you remember to take RINVOQ, take it at the same time every day.
The tablets can be taken with or without food.
Do not swallow the desiccant.
Avoid food or drink containing grapefruit whilst you are taking (or being treated with)
RINVOQ as these may make side effects more likely, by increasing the amount of medicine inyour body.

If you take more RINVOQ than you should
If you take more RINVOQ than you should, contact your doctor. You may get some of the side effects
listed in section 4.
If you forget to take RINVOQ• If you miss a dose, take it as soon as you remember.
• If you forget your dose for an entire day, just skip the missed dose and take only a single dose as
usual the following day.
• Do not take a double dose to make up for a forgotten tablet.
If you stop taking RINVOQ
Do not stop taking RINVOQ unless your doctor tells you to stop taking it.
How to open the bottle
Foil Cutting Tool - on the cap of the bottle95

1. How to puncture the foil
1a. Remove the cap from the bottle bypushing down and while still pushing, turnthe cap anti-clockwise.
1b. Turn the cap over and place the cutting
tool near the edge of the foil seal.

2. Push down to make a hole in the foil andmove the cutting tool round the edge of the
foil to continue cutting the foil.

3. When you have taken your tablet, put thecap back on and close the bottle.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.

Possible side effects

Like all medicines, RINVOQ can cause side effects, although not everybody gets them.
Serious side effects
Talk to your doctor or get medical help straight away if you get any signs of:•
infection such as shingles or painful skin rash with blisters (herpes zoster) – common (mayaffect up to 1 in 10 people)•
infection of the lung (pneumonia), which may cause shortness of breath, fever, and a cough withmucus – common (may affect up to 1 in 10 people)•
infection in the blood (sepsis) – uncommon (may affect up to 1 in 100 people)•
allergic reaction (chest tightness, wheezing, swelling of the lips, tongue or throat, hives) –uncommon (may affect up to 1 in 100 people)
Other side effects
Talk to your doctor if you notice any of the following side effects:
Very common (may affect more than 1 in 10 people)•
throat and nose infections•
acne
Common (may affect up to 1 in 10 people)•
non-melanoma skin cancer
•
cough
•
fever
•
cold sores (herpes simplex)•
feeling sick in the stomach (nausea)
96

•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•

increase in an enzyme called creatine kinase, shown by blood tests
low white blood cell counts shown in blood tests
increased levels of cholesterol (a type of fat in the blood) as shown in tests
increased levels of liver enzymes, shown by blood tests (sign of liver problems)
weight gain
inflammation (swelling) of the hair follicles
flu (influenza)
anaemia
pain in your belly (abdomen)
fatigue (feeling unusually tired and weak)
headachehives (urticaria)
urinary tract infectionrasha spinning sensation (vertigo)
dizziness

Uncommon (may affect up to 1 in 100 people)•
thrush in the mouth (white patches in the mouth)•
increased levels of triglycerides (a type of fat) in the blood, as shown in tests•
diverticulitis (painful inflammation of small pockets in the lining of your intestine)•
gastrointestinal perforation (a hole in the bowel)
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side
effects not listed in this leaflet. You can also report side effects directly via the national reporting
system listed in Appendix V. By reporting side effects you can help provide more information on thesafety of this medicine.
5.

How to store RINVOQ

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister label and carton after‘EXP’.
This medicine does not require any special temperature storage conditions.
Store in original blister or bottle with the lid tightly closed to protect from moisture.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how tothrow away medicines you no longer use. These measures will help protect the environment.
6.

Contents of the pack and other information

What RINVOQ contains
The active substance is upadacitinib.
RINVOQ 15 mg prolonged-release tablets•
Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg
upadacitinib.
•
The other ingredients are:
97

•
•

Core tablet: microcrystalline cellulose, mannitol, tartaric acid, hypromellose, silica
colloidal anhydrous, magnesium stearate.
Film coating: poly(vinyl alcohol), macrogol, talc, titanium dioxide (E171), iron oxide red(E172), iron oxide black (E172).

RINVOQ 30 mg prolonged-release tablets•
Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg
upadacitinib.
•
The other ingredients are:• Core tablet: microcrystalline cellulose, mannitol, tartaric acid, hypromellose, silica
colloidal anhydrous, magnesium stearate.
• Film coating: poly(vinyl alcohol), macrogol, talc, titanium dioxide (E171), iron oxide red(E172).
RINVOQ 45 mg prolonged-release tablets•
Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 45 mg
upadacitinib.
•
The other ingredients are:• Core tablet: microcrystalline cellulose, mannitol, tartaric acid, hypromellose, silica
colloidal anhydrous, magnesium stearate.
• Film coating: poly(vinyl alcohol), macrogol, talc, titanium dioxide (E171), iron oxide
yellow (E172) and iron oxide red (E172).
What RINVOQ looks like and contents of the pack
RINVOQ 15 mg prolonged-release tablets
RINVOQ 15 mg prolonged-release tablets are purple, oblong, biconvex tablets imprinted on one sidewith ‘a15’.
The tablets are provided in blisters or bottles.
RINVOQ is available in packs containing 28 or 98 prolonged-release tablets and in multipacks of 84
comprising 3 cartons, each containing 28 prolonged-release tablets.
Each calendar blister contains 7 tablets.
RINVOQ is available in bottles with desiccant containing 30 prolonged-release tablets, each packcontains 1 bottle (30 tablet pack) or 3 bottles (90 tablet pack).
RINVOQ 30 mg prolonged-release tablets
RINVOQ 30 mg prolonged-release tablets are red, oblong, biconvex tablets imprinted on one side with‘a30’.
The tablets are provided in blisters or bottles.
RINVOQ is available in packs containing 28 or 98 prolonged-release tablets.
Each calendar blister contains 7 tablets.
RINVOQ is available in bottles with desiccant containing 30 prolonged-release tablets, each packcontains 1 bottle (30 tablet pack) or 3 bottles (90 tablet pack).
RINVOQ 45 mg prolonged-release tablets
RINVOQ 45 mg prolonged-release tablets are yellow to mottled yellow, oblong, biconvex tablets
imprinted on one side with ‘a45’.

98

The tablets are provided in blisters or bottles.
RINVOQ is available in packs containing 28 prolonged-release tablets.
Each calendar blister contains 7 tablets.
RINVOQ is available in bottles with desiccant containing 28 prolonged-release tablets, each packcontains 1 bottle.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
Manufacturer
AbbVie S.r.l.
S.R. 148 Pontina, km 52 SNC
04011 Campoverde di Aprilia (Latina)
Italy
AbbVie Logistics B.V.
Zuiderzeelaan 53
Zwolle, 8017 JV,Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
AbbVie SA
Tél/Tel: +32 10 477811

Lietuva
AbbVie UAB
Tel: +370 5 205 3023

България
АбВи ЕООД
Тел.:+359 2 90 30 430

Luxembourg/Luxemburg
AbbVie SA
Belgique/Belgien
Tél/Tel: +32 10 477811

Česká republika
AbbVie s.r.o.
Tel: +420 233 098 111

Magyarország
AbbVie Kft.
Tel.:+36 1 455 8600

Danmark
AbbVie A/S
Tlf: +45 72 30-20-28

Malta
V.J.Salomone Pharma Limited
Tel: +356 22983201

Deutschland
AbbVie Deutschland GmbH & Co. KG
Tel: 00800 222843 33 (gebührenfrei)
Tel: +49 (0) 611 / 1720-0

Nederland
AbbVie B.V.
Tel: +31 (0)88 322 2843

99

Eesti
AbbVie OÜ
Tel: +372 623 1011

Norge
AbbVie AS
Tlf: +47 67 81 80 00ΕλλάδαAbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε.
Τηλ: +30 214 4165 555

Österreich
AbbVie GmbH
Tel: +43 1 20589-0

EspañaAbbVie Spain, S.L.U.
Tel: +34 91 384 09 10

PolskaAbbVie Sp. z o.o.
Tel.: +48 22 372 78 00

France
AbbVieTél: +33 (0) 1 45 60 13 00

Portugal
AbbVie, Lda.
Tel: +351 (0)21 1908400

Hrvatska
AbbVie d.o.o.
Tel + 385 (0)1 5625 501

România
AbbVie S.R.L.
Tel: +40 21 529 30 35

Ireland
AbbVie Limited
Tel: +353 (0)1 4287900

Slovenija
AbbVie Biofarmacevtska družba d.o.o.
Tel: +386 (1)32 08 060

ÍslandVistor hf.
Sími: +354 535 7000

Slovenská republika
AbbVie s.r.o.
Tel: +421 2 5050 0777

ItaliaAbbVie S.r.l.
Tel: +39 06 928921

Suomi/Finland
AbbVie Oy
Puh/Tel: +358 (0)10 2411 200Κύπρος
Lifepharma (Z.A.M.) LtdΤηλ.: +357 22 34 74 40

Sverige
AbbVie AB
Tel: +46 (0)8 684 44 600

Latvija
AbbVie SIA
Tel: +371 67605000

United Kingdom (Northern Ireland)
AbbVie Deutschland GmbH & Co. KG
Tel: +44 (0)1628 561090

This leaflet was last revised in
Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
Detailed and updated information on this product is also available by scanning the QR code included
below or on the outer carton with a smart phone. The same information is also available on thefollowing URL: www.rinvoq.eu.
QR code to be included
To listen to or request a copy of this leaflet in <Braille>, <large print> or <audio>, please contact
the local representative of the Marketing Authorisation Holder.
100