Rinvoq

Upadacitinib.

Each extended-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg of upadacitinib.
Excipients/Inactive Ingredients: Tablet contents: Microcrystalline cellulose, Hypromellose, Mannitol, Tartaric acid, Colloidal anhydrous silica, Magnesium stearate.
Film coating: Poly(vinyl alcohol), Macrogol, Talc, Titanium dioxide (E171), Iron oxide black (E172) (15 mg strength only), Iron oxide red (E172).

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants. ATC code: L04AA44.
Pharmacology: Pharmacodynamics: Mechanism of Action: Upadacitinib is a selective and reversible Janus Kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit cytokine or growth factor signals involved in a broad range of cellular processes including inflammatory responses, hematopoiesis and immune surveillance. The JAK family of enzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylate and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function.
In human cellular assays, upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Atopic dermatitis is driven by pro-inflammatory cytokines (including IL-4, IL-13, IL-22, TSLP, IL-31 and IFN-γ) that transduce signals via the JAK1 pathway. Inhibiting JAK1 with upadacitinib reduces the signaling of many mediators which drive the signs and symptoms of atopic dermatitis such as eczematous skin lesions and pruritus.
Pharmacodynamic effects: Inhibition of IL-6 Induced STAT3 and IL-7 Induced STAT5 Phosphorylation: In healthy volunteers, the administration of upadacitinib (immediate release formulation) resulted in a dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2)-induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. The maximal inhibition was observed 1 hour after dosing which returned to near baseline by the end of dosing interval.
Lymphocytes: In patients with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline up to Week 36 which gradually returned to at or near baseline levels with continued treatment.
hsCRP: In patients with rheumatoid arthritis, treatment with upadacitinib was associated with decreases from baseline in mean hsCRP levels as early as Week 1 which were maintained with continued treatment.
Vaccine Study: The influence of upadacitinib on the humoral response following the administration of inactivated pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) was evaluated in 111 patients with 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 of patients with satisfactory humoral response defined as ≥2-fold increase in antibody concentration from 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 1). Patients 18 years of age and older were eligible to participate. The presence of at least 6 tender and 6 swollen joints and evidence of systemic inflammation based on elevation of hsCRP was required at baseline. 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 drug, 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 that observed with upadacitinib 30 mg QD. (See Table 1.)

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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 to placebo, MTX or adalimumab (Table 2). 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 treatment of 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 through 3 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 2). 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 and physician global assessments, HAQ-DI, pain assessment and hsCRP. (See Table 2.)

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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 and week 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 and as monotherapy compared to MTX in SELECT-EARLY (Table 3). Analyses of erosion and joint space narrowing scores were consistent with the overall scores. The proportion of patients with no radiographic progression (mTSS change ≤ 0) was significantly higher with upadacitinib 15 mg in both studies. Inhibition of progression of structural joint damage was maintained through Week 96 in both studies for patients who remained on their originally allocated treatment with upadacitinib 15 mg (based on available results from 327 patients in SELECT-COMPARE and 238 patients in SELECT-EARLY). (See Table 3.)

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Physical Function Response and Health-Related Outcomes: Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted in a significantly greater improvement in physical function compared to all comparators as measured by HAQ-DI (see Table 4).
Improvements in HAQ-DI and pain were maintained through 3 years for patients who remained on their originally allocated treatment with upadacitinib 15 mg based on available results from SELECT-COMPARE and SELECT-EARLY. (See Table 4.)

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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 of morning joint stiffness compared to placebo or MTX.
In the clinical studies, upadacitinib treated patients reported significant improvements in patient-reported quality of life, as measured by the Short Form (36) Health Survey (SF-36) Physical Component Score 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, multicenter, placebo-controlled studies in patients 18 years of age or older with moderately to severely active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender joints and at least 3 swollen joints, and active plaque psoriasis or history of plaque psoriasis. For both studies, 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 to at 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 to at least one biologic DMARD. At baseline, 296 (46%) of patients were on at least one concomitant non-biologic DMARD; 222 (35%) of patients received concomitant MTX only; and 345 (54%) of patients 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 5). 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.
In both studies, consistent responses were observed alone or in combination with methotrexate for primary 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). (See Table 5.)

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Radiographic response: In SELECT-PsA 1, inhibition of progression of structural damage was assessed radiographically and expressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, the erosion score and the joint space narrowing score, at week 24.
Treatment with upadacitinib 15 mg resulted in statistically significant greater inhibition of the progression of structural joint damage compared to placebo at week 24 (Table 6). Erosion and joint space narrowing scores were consistent with the overall scores. The proportion of patients with no radiographic progression (mTSS change ≤ 0.5) was higher with upadacitinib 15 mg compared to placebo at week 24. (See Table 6.)

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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 with adalimumab 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% CI: -0.37, -0.24]) compared to placebo (-0.10 [95% CI: -0.16, -0.03]). Improvement in physical function 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 Physical Component Summary score compared to placebo at week 12. Improvements from baseline were maintained through week 56 in both studies.
Patients receiving upadacitinib 15 mg experienced statistically significant improvement from baseline in 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 and SELECT-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.
Atopic dermatitis: The efficacy and safety of upadacitinib 15 mg and 30 mg once daily was assessed in three Phase 3 randomized, double-blind, multicenter studies (MEASURE UP 1, MEASURE UP 2 and AD UP) in a total of 2584 patients 12 years of age and older (Table 7). 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 matching placebo for 16 weeks. In the AD UP study, patients also received concomitant topical corticosteroids (TCS). Following completion of the double-blinded period, patients originally randomized to upadacitinib were to continue receiving the same dose until week 260. Patients in the placebo group were re-randomized in a 1:1 ratio to receive upadacitinib 15 mg or 30 mg until week 260. (See Table 7.)

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Clinical Response: Monotherapy Studies (MEASURE UP 1 AND MEASURE UP 2): In the MEASURE UP studies, a significantly greater proportion of patients treated with upadacitinib 15 mg or 30 mg achieved vIGA-AD 0 or 1 response and achieved EASI 75 compared to placebo at week 16 (Table 8). A rapid improvement in skin clearance (defined as EASI 75 by week 2) was achieved for both doses compared to placebo (p < 0.001).
A significantly greater proportion of patients treated with upadacitinib 15 mg or 30 mg achieved clinically meaningful improvement in itch (defined as a ≥4-point reduction in the Worst Pruritus NRS) compared to placebo at week 16. Rapid improvement in itch (defined as a ≥4-point reduction in Worst Pruritus NRS by week 1) was achieved for both doses compared to placebo (p < 0.001), with differences observed as early as 1 day after initiating upadacitinib 30 mg (Day 2, p < 0.001) and 2 days after initiating upadacitinib 15 mg (Day 3, p < 0.001).
A significantly smaller proportion of patients treated with upadacitinib 15 mg or 30 mg had a disease flare, defined as a clinically meaningful worsening of disease (increase in EASI by ≥6.6), during the initial 16 weeks of treatment compared to placebo (p < 0.001).
Figure 1 and Figure 2 show proportion of patients achieving an EASI 75 response and the proportion of patients with ≥4-point improvement in the Worst Pruritus NRS, respectively up to week 16. (See Table 8, Figures 1 and 2.)

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In both studies, results at week 16 continued to be observed through week 52 in patients treated with upadacitinib 15 mg or 30 mg.
Treatment effects in subgroups (weight, age, gender, race, and prior systemic treatment with immunosuppressants) in both studies were consistent with the results in the overall study population.
Concomitant TCS Study (AD UP): In AD UP, a significantly greater proportion of patients treated with upadacitinib 15 mg + TCS or 30 mg + TCS achieved vIGA-AD 0 or 1 response and achieved EASI 75 compared to placebo + TCS at week 16 (Table 9). A rapid improvement in skin clearance (defined as EASI 75 by week 2) was achieved for both doses compared to placebo + TCS (p < 0.001). In addition, a higher EASI 90 response rate was achieved at week 4 for both doses compared to placebo + TCS (p < 0.001).
A significantly greater proportion of patients treated with upadacitinib 15 mg + TCS or 30 mg + TCS achieved a clinically meaningful improvement in itch (defined as a ≥4-point reduction in the Worst Pruritus NRS) compared to placebo + TCS at week 16. A rapid improvement in itch (defined as a ≥4-point reduction in Worst Pruritus NRS by week 1) was achieved for both doses compared to placebo + TCS (p < 0.001).
Figure 3 and Figure 4 show proportion of patients achieving an EASI 75 response and the proportion of patients with ≥4-point improvement in the Worst Pruritus NRS, respectively up to week 16. (See Table 9, Figures 3 and 4.)

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Treatment effects in subgroups (weight, age, gender, race, and prior systemic treatment with immunosuppressants) in AD UP were consistent with the results in the overall study population.
Subjects treated with either upadacitinib 15 mg or 30 mg had significantly more days free of TCS use with a concurrent EASI 75 response (mean: 33.5 and 47.5 days, respectively) over the 16-week period, compared to placebo group (mean: 7.9 days).
Results at week 16 continued to be observed through week 52 in patients treated with upadacitinib 15 mg or 30 mg.
Quality of Life/Patient reported outcomes: In the MEASURE UP studies, a significantly greater proportion of patients treated with upadacitinib 15 mg or 30 mg reported clinically meaningful reductions in the symptoms of AD and the impact of AD on health-related quality of life compared to placebo at week 16 (Table 10). A significantly greater proportion of patients treated with upadacitinib achieved clinically meaningful reductions in AD symptom severity as measured by ADerm-SS TSS-7 and ADerm-SS Skin Pain compared to placebo at week 16. A greater proportion of patients treated with upadacitinib achieved clinically meaningful reductions in the patient-reported effects of AD on sleep, daily activities and emotional state as measured by the ADerm-IS domain scores compared to placebo at week 16. Similarly, compared to placebo at week 16, a greater proportion of patients treated with upadacitinib achieved clinically meaningful improvements in AD symptom frequency and health-related quality of life as measured by the POEM and DLQI.
Anxiety and depression symptoms as measured by the HADS score were significantly reduced; in patients with baseline HADS-anxiety or HADS-depression subscale scores ≥8 (the cut-off value for anxiety or depression), a greater proportion of patients in the upadacitinib 15 mg or 30 mg groups achieved HADS-anxiety and HADS-depression scores <8 at week 16 compared to placebo (Table 10). (See Table 10.)

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Paediatric population: A total of 344 adolescents aged 12 to 17 years with moderate to severe atopic dermatitis were randomized 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 topical corticosteroids. Efficacy was consistent between the adolescents and adults (Table 11). The adverse event profile in adolescents was generally similar to that in adults. Safety and efficacy of upadacitinib in adolescents weighing less than 40 kg and in patients less than 12 years of age with atopic dermatitis have not been established. (See Table 11.)

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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, juvenile idiopathic arthritis and atopic dermatitis) (see Dosage & Administration for information on paediatric use).
Ankylosing Spondylitis (AS, radiographic axial spondyloarthritis): The efficacy and safety of RINVOQ 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 long-term extensions for up to 2 years.
SELECT-AXIS 1 was a 14-week placebo-controlled trial in 187 ankylosing spondylitis patients with an inadequate response to at least two NSAIDs or intolerance to or contraindication for NSAIDs and had no previous exposure to biologic DMARDs. At baseline, patients had symptoms of ankylosing spondylitis for an average of 14.4 years and approximately 16% of the patients were on a concomitant 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 patients achieving an Assessment of SpondylArthritis international Society 40 (ASAS40) response at week 14.
SELECT-AXIS 2 (AS) was a 14-week placebo-controlled trial in 420 ankylosing spondylitis patients with prior exposure to bDMARDs (77.4% had lack of efficacy to either a tumour necrosis factor (TNF) blocker or interleukin-17 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 patients achieving an Assessment of SpondylArthritis international Society 40 (ASAS40) response at week 14.
Clinical Response: In both studies, a significantly greater proportion of patients treated with RINVOQ 15 mg achieved an ASAS40 response compared to placebo at Week 14 (Table 12). 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 RINVOQ 15 mg resulted in improvements in individual ASAS components, (patient global assessment of disease activity, total back pain assessment, inflammation, and function) and other 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. (See Table 12.)

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In SELECT-AXIS 1, efficacy was maintained through 2 years as assessed by the endpoints presented in Table 12.
Physical Function Response and Health-Related Outcomes: In both studies, patients treated with RINVOQ 15 mg showed significant improvement in physical function from baseline compared to placebo as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI) change from baseline at week 14. In SELECT-AXIS 1, improvement in BASFI was maintained through 2 years.
In SELECT-AXIS 2 (AS), patients treated with RINVOQ 15 mg showed significant improvements in total back pain and nocturnal back pain compared to placebo at Week 14.
In SELECT-AXIS 2 (AS), patients treated with RINVOQ 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.
Enthesitis: In SELECT-AXIS 2, patients with pre-existing enthesitis (n=310) treated with RINVOQ 15 mg showed significant improvement in enthesitis compared to placebo as measured by change from baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at week 14.
Spinal mobility: In SELECT-AXIS 2 (AS), patients treated with RINVOQ 15 mg showed significant improvement in spinal mobility compared to placebo as measured by change from baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 14.
Objective Measures of Inflammation: Signs of inflammation were assessed by MRI and expressed as change from baseline in the SPARCC score for spine and sacroiliac joints. In both studies, at Week 14, significant improvement of inflammatory signs in the spine was observed in patients treated with RINVOQ 15 mg compared to placebo. In SELECT-AXIS 1, improvement in inflammation as assessed by MRI was maintained through 2 years.
Pharmacokinetics: Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after multiple once-daily administrations.
Absorption: Following oral administration of upadacitinib extended-release formulation, upadacitinib is absorbed with a median T_max 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%). In clinical trials, upadacitinib was administered without regard to meals (see Dosage & Administration). In vitro, upadacitinib is a substrate for the efflux transporters P-gp and BCRP.
Distribution: Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components, as indicated by the blood to plasma ratio of 1.0.
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 human radiolabeled study, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma while the main metabolite (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.
Elimination: Following single dose administration of [¹⁴C]-upadacitinib immediate-release solution, upadacitinib was eliminated predominantly as the unchanged parent substance in urine (24%) and faeces (38%). Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminal elimination half-life ranged from 9 to 14 hours.
Special populations: Renal impairment: Upadacitinib 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 C_max was similar in subjects with normal and impaired renal function. Mild or moderate renal impairment has no clinically relevant effect on upadacitinib exposure following the 15 mg or 30 mg once daily dosing regimens. The recommended dose is 15 mg once daily for patients with severe renal impairment.
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 mild and moderate hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib C_max was unchanged in subjects with mild hepatic impairment and 43% higher in subjects 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 a paediatric patients with rheumatoid arthritis and psoriatic arthritis (see Dosage & Administration). Upadacitinib pharmacokinetics and steady-state concentrations are similar for adults and adolescents 12 to 17 years of age with atopic dermatitis.
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, atopic dermatitis and ankylosing spondylitis patients.
Toxicology: Preclinical safety data: Upadacitinib, at exposures (based on AUC) approximately 4 and 10 times the clinical dose of 15 mg and 2 and 5 times the clinical dose of 30 mg in male and female Sprague-Dawley rats, respectively, was not carcinogenic in a 2-year carcinogenicity study in Sprague-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 gene mutations and chromosomal aberrations.
Upadacitinib had no effect on fertility in male or female rats at exposures up to approximately 21 and 43 times the maximum recommended human dose (MRHD) of 30 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 were observed at exposures below clinical exposure (based on AUC). Post-implantation losses were observed at exposures 11 times the clinical exposure at the MRHD of 30 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 and 0.8 times the clinical exposure (AUC-based) at the 15 and 30 mg (MRHD) doses, respectively. In rabbits an increased incidence of cardiovascular malformations was observed at 15 and 7.6 times the clinical exposure at the 15 and 30 mg doses (AUC-based), respectively. No developmental toxicity was observed at approximately 0.15 times (rat) and at similar exposure in rabbits as the exposures at the MRHD of 30 mg. In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 1.4 times the MRHD of 30 mg resulted in no maternal effects, no effects on parturition, lactation or maternal behaviour and no effects on the offspring.
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 the parent molecule, upadacitinib.
Administration of upadacitinib to juvenile Sprague-Dawley rats (from postnatal day 15 to 63) resulted in exposures and pharmacologic effects on the lymphoid system similar to those observed in adult rats. No adverse findings were observed in juvenile rats at exposures (AUC) approximately 9.4 and 4.8 times the exposures at the clinical doses of 15 mg and 30 mg, respectively (based on exposures in adult RA patients).

Rheumatoid arthritis: RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.
Psoriatic arthritis: RINVOQ is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate.
Atopic dermatitis: RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.
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.

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 ankylosing spondylitis: The recommended dose of upadacitinib is 15 mg once daily.
Consideration should be given to discontinuing treatment in patients with ankylosing spondylitis 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.
Atopic dermatitis: Adults: The recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patient presentation.
A dose of 30 mg once daily may be appropriate for patients with high disease burden.
A dose of 30 mg once daily may be appropriate for patients with an inadequate response to 15 mg once daily.
The lowest effective dose for maintenance should be considered.
For patients ≥65 years of age, the recommended dose is 15 mg once daily.
Adolescents (from 12 to 17 years of age): The recommended dose of upadacitinib is 15 mg once daily for adolescents weighing at least 40 kg.
RINVOQ has not been studied in adolescents weighing less than 40 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.
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 Precautions and Adverse Reactions).
Dose Interruption: Treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 13. (See Table 13.)

Click on icon to see table/diagram/image

Special populations: Elderly: For atopic dermatitis, doses higher than 15 mg once daily are not recommended in patients aged 65 years and older (see Adverse Reactions).
There are limited data in patients aged 75 years and older.
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 Pharmacology: Pharmacokinetics under Actions). Upadacitinib 15 mg once daily should be used with caution in patients with severe renal impairment. Upadacitinib 30 mg once daily is not recommended for patients with severe renal impairment. The use of upadacitinib has not been studied in subjects with end stage renal disease.
Hepatic Impairment: No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions). Upadacitinib should not be used in patients with severe (Child Pugh C) hepatic impairment (see Contraindications).
Paediatric population: The safety and efficacy of RINVOQ in adolescents weighing < 40 kg and in children aged 0 to less than 12 years have not yet been established. No data are available.
The safety and efficacy of RINVOQ in children and adolescents with rheumatoid arthritis and psoriatic arthritis 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 the day. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensure the entire dose is delivered correctly.
Missed Dose: If a dose of RINVOQ is missed and it is more than 10 hours from the next scheduled dose, advise the patient to take a dose as soon as possible and then to take the next dose at the usual time. If a dose is missed and it is less than 10 hours from the next scheduled dose, advise the patient to skip the missed dose and take only a single dose as usual the following day. Advise the patient not to double a dose to make up for a missed dose.

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

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Active tuberculosis (TB) or active serious infections (see Precautions).
Severe hepatic impairment (see Dosage & Administration).
Pregnancy (see Use in Pregnancy & Lactation).

Immunosuppressive Medicinal Products: Combination with other potent immunosuppressants such as azathioprine, ciclosporin, tacrolimus, and biologic DMARDs or other Janus kinase (JAK) inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.
Serious Infections: Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported with upadacitinib included pneumonia and cellulitis (see Adverse Reactions). Cases of bacterial meningitis 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; or with underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with upadacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and upadacitinib therapy should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib therapy may be resumed once the infection is controlled.
As there is a higher incidence of infections in the elderly ≥ 65 years of age, caution should be used when treating this population.
Tuberculosis: Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinib should not be given to patients with active TB (see Contraindications). Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with risk factors for TB infection.
Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.
Patients should be monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.
Viral Reactivation: Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical studies (see Adverse Reactions). The risk of herpes zoster appears to be higher in patients treated with RINVOQ in Japan. If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves.
Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.
Vaccination: No data are available on the response to vaccination with live vaccines in patients receiving upadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended. Prior to initiating upadacitinib, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines (see Pharmacology under Actions for data on inactivated pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) and concomitant use with upadacitinib).
Malignancy: The risk of malignancies, including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies, including lymphoma. The clinical data are currently limited and long-term studies are ongoing.
In a large randomized active-controlled study in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, an increased incidence of malignancy, particularly lung cancer, lymphoma and non-melanoma skin cancer [NMSC], was observed with tofacitinib (a different JAK inhibitor) compared to Tumor Necrosis Factor (TNF) blockers.
Malignancies were observed in clinical studies of upadacitinib. A higher rate of malignancies, driven by NMSC, was observed with RINVOQ 30 mg compared to RINVOQ 15 mg. The risks and benefits of upadacitinib treatment should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated NMSC or when considering continuing upadacitinib therapy in patients who develop a malignancy.
Non-melanoma skin cancer: NMSCs have been reported in patients treated with upadacitinib. Periodic skin examination is recommended for patients who are at increased risk 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 Adverse Reactions). Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1 x 10⁹ cells/L, ALC < 0.5 x 10⁹ cells/L or haemoglobin < 8 g/dL observed during routine patient management (see Dosage & Administration).
Major Adverse Cardiovascular Events (MACE): In a large randomized active-controlled study in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, an increased incidence of MACE, including myocardial infarction (MI), was observed with tofacitinib (a different JAK inhibitor) compared with TNF blockers.
Consider the risks and benefits of RINVOQ treatment prior to initiating therapy in patients with cardiovascular risk factors or when considering continuing RINVOQ in patients who develop MACE.
Lipids: Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see Adverse Reactions). 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 Dosage & Administration for monitoring guidance).
Hepatic transaminase elevations: Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared 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) have been reported in patients receiving JAK inhibitors including upadacitinib. In a large randomized activecontrolled study in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose-dependent increased incidence of VTE was observed with tofacitinib (a different JAK inhibitor) compared with TNF blockers.
Upadacitinib should be used with caution in patients at high risk for DVT/PE. Risk factors that should be considered in determining the patient's risk for DVT/PE include older age, obesity, a medical history of DVT/PE, patients undergoing major surgery, and prolonged immobilisation. If clinical features of DVT/PE occur, upadacitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.
Hypersensitivity Reactions: Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy (see Adverse Reactions).
Gastrointestinal Perforations: Events of gastrointestinal perforations have been reported in clinical trials (see ADVERSE REACTIONS) and from post-marketing sources. RINVOQ should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or opioids). Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
Effects on ability to drive and use machines: Upadacitinib has no or negligible influence on the ability to drive and use machines.

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 their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib.
Pregnancy: There are no or limited data on the use of upadacitinib in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Upadacitinib was teratogenic in rats and rabbits with effects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero.
Upadacitinib is contraindicated during pregnancy (see Contraindications).
If a patient becomes pregnant while taking upadacitinib the parents should be informed of the potential risk to the foetus.
Breast-feeding: It is unknown whether upadacitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see Pharmacology: Toxicology: Preclinical safety data under Actions).
A risk to newborns/infants cannot be excluded.
Upadacitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue upadacitinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: The effect of upadacitinib on human fertility has not been evaluated. Animal studies do not indicate effects with respect to fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: In rheumatologic disease clinical trials, the most commonly reported adverse drug reactions (ADRs) were upper respiratory tract infections, bronchitis, nausea, blood creatine phosphokinase (CPK) increased and cough. The most common serious adverse reactions were serious infections (see Precautions).
Tabulated list of adverse reactions: The following list of adverse reactions is based on experience from clinical studies. The frequency of adverse reactions listed as follows 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 in Table 14 are based on the higher of the rates for adverse reactions reported with RINVOQ 15 mg in rheumatologic disease and atopic dermatitis clinical trials, or RINVOQ 30 mg in atopic dermatitis clinical trials. When notable differences in frequency were observed between indications, these are presented in the footnotes below the table. (See Table 14.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Rheumatoid arthritis: Infections: In placebo-controlled clinical studies with background DMARDs, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg group was 27.4% compared to 20.9% in the placebo group. In methotrexate (MTX)-controlled studies, the frequency of infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 19.5% compared to 24.0% in the MTX group. The overall long-term rate of infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies (2,630 patients) was 93.7 events per 100 patient-years.
In placebo-controlled clinical studies with background DMARDs, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg group was 1.2% compared to 0.6% in the placebo group. In MTX-controlled studies, the frequency of serious infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group was 0.6% compared to 0.4% in the MTX group. The overall long-term rate of serious infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.8 events per 100 patient-years. The most common serious infection was pneumonia. The rate of serious infections remained stable with long-term exposure.
There was a higher rate of serious infections in patients ≥ 75 years of age, although data are limited.
Opportunistic infections (excluding tuberculosis): In placebo-controlled clinical studies with background DMARDs, the frequency of opportunistic infections over 12/14 weeks in the upadacitinib 15 mg group was 0.5% compared to 0.3% in the placebo group. In MTX-controlled studies, there were no cases of opportunistic infection over 12/14 weeks in the upadacitinib 15 mg monotherapy group and 0.2% in the MTX group. The overall long-term rate of opportunistic infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 0.6 events per 100 patient-years.
The long-term rate of herpes zoster for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.7 events per 100 patient-years. Most of the herpes zoster events involved a single dermatome and were non-serious.
Hepatic transaminase elevations: In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with upadacitinib 15 mg, compared to 1.5% and 0.7%, respectively, of patients treated with placebo. 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, compared to 1.9% and 0.9%, respectively, of patients treated with MTX.
The pattern and incidence of elevation in ALT/AST remained stable over time including in long term extension studies.
Lipid elevations: Upadacitinib 15 mg treatment was associated with increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 2 to 4 weeks of treatment and remained stable with longer-term treatment. Among patients in the controlled studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 12/14 weeks (including patients who had an isolated elevated value): Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 62% vs. 31%, in the upadacitinib 15 mg and placebo groups, respectively.
LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 42% vs. 19%, in the upadacitinib 15 mg and placebo groups, respectively.
HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 89% vs. 61%, in the upadacitinib 15 mg and placebo groups, respectively.
Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 25% vs. 15%, in the upadacitinib 15 mg and placebo groups, respectively.
Creatine phosphokinase: In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, increases in CPK values were observed. CPK elevations > 5 x upper limit of normal (ULN) were reported in 1.0% and 0.3% of patients over 12/14 weeks in the upadacitinib 15 mg and placebo groups, respectively. Most elevations > 5 x ULN were transient and did not require treatment discontinuation. Mean CPK values increased by 4 weeks with a mean increase of 60 U/L at 12 weeks and then remained stable at an increased value thereafter including with extended therapy.
Neutropaenia: In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in neutrophil counts below 1 x 10⁹ cells/L in at least one measurement occurred in 1.1% and <0.1% of patients in the upadacitinib 15 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ANC < 1 x 10⁹ cells/L (see Dosage & Administration). 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 incidence of acne and bronchitis was observed in patients treated with upadacitinib 15 mg (1.3% and 3.9%, respectively) compared to placebo (0.3% and 2.7%, respectively). A higher rate of serious infections (2.6 events per 100 patient-years and 1.3 events per 100 patient-years, respectively) and hepatic transaminase elevations (ALT elevations Grade 3 and higher rates 1.4% and 0.4%, respectively) was observed in patients treated with upadacitinib in combination with MTX therapy compared to patients treated with monotherapy. There was a higher rate of serious infections in patients ≥ 65 years of age, although data are limited.
Atopic dermatitis: Infections: In the placebo-controlled period of the clinical studies, the frequency of infection over 16 weeks in the upadacitinib 15 mg and 30 mg groups was 39% and 43% compared to 30% in the placebo group, respectively. The long-term rate of infections 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 the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.4% compared to 0.6% in the placebo group, respectively. The long-term rate of serious infections 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 and herpes 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 placebo group, respectively. The long-term rate of eczema herpeticum for the upadacitinib 15 mg and 30 mg groups 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.
Elderly: Based on limited data in atopic dermatitis patients aged 65 years and older, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose.
Paediatric population: A total of 343 adolescents aged 12 to 17 years with atopic dermatitis were treated in the Phase 3 studies, of which 167 were exposed to 15 mg. The safety profile for upadacitinib 15 mg in adolescents was similar to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated.
Ankylosing Spondylitis: Overall, the safety profile observed in patients with active ankylosing spondylitis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. No new safety findings were identified.
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.

Potential for other medicinal products to affect the pharmacokinetics of upadacitinib: Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can be affected by medicinal products that strongly inhibit or induce CYP3A4.
Coadministration with CYP3A4 Inhibitors: Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, and clarithromycin and grapefruit). In a clinical study, coadministration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib C_max 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 receiving chronic treatment with strong CYP3A4 inhibitors. 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 as rifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinical study, coadministration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer) resulted in approximately 50% and 60% decreases in upadacitinib C_max and AUC, respectively. Patients should be monitored for changes in disease activity if upadacitinib is co-administered with strong CYP3A4 inducers.
Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures.
Potential for upadacitinib to affect the pharmacokinetics of other medicinal products: Administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects had a limited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (26% decrease in midazolam AUC and C_max), indicating that upadacitinib 30 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 administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevant effect on atorvastatin C_max or on plasma exposures of ortho-hydroxyatorvastatin (major active metabolite for atorvastatin). No dose adjustment is recommended for CYP3A substrates or for rosuvastatin or atorvastatin when co-administered 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, CYP2C19, or CYP2D6.

Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at or below 30°C.
Store in the original blister in order to protect from moisture.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants / Other Dermatologicals

L04AF03 - upadacitinib ; Belongs to the class of Janus-associated kinase (JAK) inhibitors. Used as immunosuppressants.

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