Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
Upadacitinib should only be used if no suitable treatment alternatives are available in patients:
Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients 65 years of age and older, as observed in a large randomised study of tofacitinib (another Janus Kinase (JAK) inhibitor), upadacitinib should only be used in these patients if no suitable treatment alternatives are available.
In patients 65 years of age and older, there is an increased risk of adverse reactions with upadacitinib 30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is 15 mg once daily (see sections 4.2 and 4.8).
Combination with other potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.
Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported with upadacitinib included pneumonia and cellulitis (see section 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:
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with upadacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and upadacitinib therapy should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib therapy may be resumed once the infection is controlled.
A higher rate of serious infections was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients 65 years of age and older, upadacitinib should only be used if no suitable treatment alternatives are available (see section 4.2).
Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinib should not be given to patients with active TB (see section 4.3). Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with risk factors for TB infection.
Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.
Patients should be monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical studies (see section 4.8). The risk of herpes zoster appears to be higher in Japanese patients treated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves.
Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.
No data are available on the response to vaccination with live vaccines in patients receiving upadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended. Prior to initiating upadacitinib treatment, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines (see section 5.1 for data on adjuvanted recombinant glycoprotein E herpes zoster vaccine and inactivated pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) and concomitant use with upadacitinib).
Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including upadacitinib.
In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.
A higher rate of malignancies was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.
In patients 65 years of age and older, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g., current malignancy or history of malignancy) upadacitinib should only be used if no suitable treatment alternatives are available.
NMSCs have been reported in patients treated with upadacitinib (see section 4.8). A higher rate of NMSC was observed with upadacitinib 30 mg compared to upadacitinib 15 mg. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Absolute Neutrophil Count (ANC) <1 × 109 cells/L, Absolute Lymphocyte Count (ALC) <0.5 × 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 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL observed during routine patient management (see section 4.2).
Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and from post-marketing sources (see section 4.8).
Upadacitinib should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or opioids). Patients with active Crohn’s disease are at increased risk for developing intestinal perforation. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.
Events of MACE were observed in clinical studies of upadacitinib.
In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors.
Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, upadacitinib should only be used if no suitable treatment alternatives are available.
Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see section 4.8). Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined (see section 4.2 for monitoring guidance).
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.
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in clinical trials for upadacitinib.
In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose-dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to TNF inhibitors.
In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adverse cardiovascular events” and “Malignancy”) upadacitinib should only be used if no suitable treatment alternatives are available.
In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, upadacitinib should be used with caution. VTE risk factors other than cardiovascular or malignancy risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder. Patients should be re-evaluated periodically during upadacitinib treatment to assess for changes in VTE risk. Promptly evaluate patients with signs and symptoms of VTE and discontinue upadacitinib in patients with suspected VTE, regardless of dose.
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).
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.
Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can be affected by medicinal products that strongly inhibit or induce CYP3A4.
Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, and grapefruit). In a clinical study, coadministration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib 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 maintenance dose 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.
Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinical study, co-administration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer) resulted in approximately 50% and 60% decreases in upadacitinib Cmax and AUC, respectively. Patients should be monitored for changes in disease activity if upadacitinib is co-administered with strong CYP3A4 inducers.
Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures.
Administration of multiple 30 mg or 45 mg once daily doses of upadacitinib to healthy subjects had a limited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (24-26% decrease in midazolam AUC and Cmax), indicating that upadacitinib 30 mg or 45 mg once daily may have a weak induction effect on CYP3A. In a clinical study, rosuvastatin and atorvastatin AUC were decreased by 33% and 23%, respectively, and rosuvastatin Cmax was decreased by 23% following the administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevant effect on atorvastatin Cmax or on plasma exposures of ortho-hydroxyatorvastatin (major active 12 metabolite for atorvastatin). Administration of multiple 45 mg once daily doses of upadacitinib to healthy subjects led to a limited increase in AUC and Cmax of dextromethorphan (sensitive CYP2D6 substrate) by 30% and 35%, respectively, indicating that upadacitinib 45 mg once daily has a weak inhibitory effect on CYP2D6. No dose adjustment is recommended for CYP3A substrates, CYP2D6 substrates, rosuvastatin or atorvastatin when 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.
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.
There are no or limited data on the use of upadacitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Upadacitinib was teratogenic in rats and rabbits with effects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero.
Upadacitinib is contraindicated during pregnancy (see section 4.3).
If a patient becomes pregnant while taking upadacitinib the parents should be informed of the potential risk to the foetus.
It is unknown whether upadacitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see section 5.3).
A risk to newborns/infants cannot be excluded.
Upadacitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue upadacitinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
The effect of upadacitinib on human fertility has not been evaluated. Animal studies do not indicate effects with respect to fertility (see section 5.3).
Upadacitinib may have a minor influence on the ability to drive and use machines because dizziness and vertigo may occur during treatment with RINVOQ (see section 4.8).
In the placebo-controlled clinical trials for rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis, the most commonly reported adverse reactions (≥2% of patients in at least one of the indications with the highest rate among indications presented) with upadacitinib 15 mg were upper respiratory tract infections (19.5%), blood creatine phosphokinase (CPK) increased (8.6%), alanine transaminase increased (4.3%), bronchitis (3.9%), nausea (3.5%), 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%), aspartate transaminase increased (3.9%), fatigue (3.9%), folliculitis (3.6%), alanine transaminase increased (3.5%), herpes simplex (3.2%), and influenza (3.2%).
The most common serious adverse reactions were serious infections (see section 4.4).
The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications.
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 in Table 3 are based on the higher of the rates for adverse reactions reported with RINVOQ in clinical trials of rheumatologic disease (15 mg), 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 differences in frequency were observed between indications, these are presented in the footnotes below the table.
Table 3. Adverse reactions:
| System Organ Class | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Upper respiratory tract infections (URTI)a | Bronchitisa,b Herpes zostera Herpes simplexa Folliculitis Influenza Urinary tract infection Pneumoniaa,h | Oral candidiasis Diverticulitis Sepsis |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Non-melanoma skin cancerf | ||
| Blood and lymphatic system disorders | Anaemiaa Neutropaeniaa Lymphopaenia | ||
| Immune system disorders | Urticariac,g | Serious hypersensitivity reactionsa,e | |
| Metabolism and nutrition disorders | Hypercholesterolaemiaa,b Hyperlipidaemiaa,b | Hypertriglyceridaemia | |
| Nervous system disorders | Headachea Dizziness | ||
| Ear and labyrinth disorders | Vertigoa | ||
| Respiratory, thoracic and mediastinal disorders | Cough | ||
| Gastrointestinal disorders | Abdominal paina,d Nausea | Gastrointestinal perforationi | |
| Skin and subcutaneous tissue disorders | Acnea,c,d,g | Rasha | |
| General disorders and administration site conditions | Fatigue Pyrexia | ||
| Investigations | Blood CPK increased ALT increasedb AST increasedb Weight increasedg |
a Presented as grouped term.
b In atopic dermatitis trials, the frequency of bronchitis, hypercholesterolaemia, hyperlipidaemia, ALT increased, and AST increased was uncommon.
c In rheumatologic disease trials, the frequency was common for acne and uncommon for urticaria.
d In ulcerative colitis trials, the frequency was common for acne; abdominal pain was less frequent for upadacitinib than for placebo.
e Serious hypersensitivity reactions including anaphylactic reaction and angioedema.
f Most events reported as basal cell carcinoma and squamous cell carcinoma of skin.
g In Crohn’s disease, the frequency was common for acne, and uncommon for urticaria and weight increased.
h Pneumonia was common in Crohn’s disease and uncommon across other indications.
i Frequency is based on Crohn’s disease clinical trials.
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.
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.
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.
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):
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.
In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases in neutrophil counts below 1 × 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 × 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.
Overall, the safety profile observed in patients with active psoriatic arthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. A higher rate of serious infections (2.6 events per 100 patient-years and 1.3 events per 100 patient-years, respectively) and hepatic transaminase elevations (ALT elevations Grade 3 and higher rates 1.4% and 0.4%, respectively) was observed in patients treated with upadacitinib in combination with MTX therapy compared to patients treated with monotherapy.
Overall, the safety profile observed in patients with active axial spondyloarthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. No new safety findings were identified.
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.
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.
Dose-dependent changes in ALT increased and/or AST increased (≥3 x ULN), lipid parameters, CPK values (>5 x ULN), and neutropaenia (ANC <1 × 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.
The overall safety profile observed in patients with ulcerative colitis was generally consistent with that observed in patients with rheumatoid arthritis.
A higher rate of herpes zoster was observed with an induction treatment period of 16 weeks vs 8 weeks.
In the placebo-controlled induction studies, the frequency of infection over 8 weeks in the upadacitinib 45 mg group compared to the placebo group was 20.7% and 17.5%, respectively. In the placebo-controlled maintenance study, the frequency of infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 38.4% and 40.6%, respectively, compared to 37.6% in the placebo group. 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 the upadacitinib 45 mg group and the placebo group was 1.3%. No additional serious infections were observed over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.2% and 2.4%, respectively, compared to 3.3% in the placebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups was 4.1 and 3.9 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance phases was COVID-19 pneumonia.
In the placebo-controlled induction studies over 8 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 45 mg group was 0.4% and 0.3% in the placebo group. No additional opportunistic infections (excluding tuberculosis and herpes zoster) were observed over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study over 52 weeks, the frequency of opportunistic infection (excluding tuberculosis and herpes zoster) in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.4%, 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 the upadacitinib 45 mg group was 0.6% and 0% in the placebo group. The frequency of herpes zoster was 3.9% over 16-week treatment with upadacitinib 45 mg. In the placebo-controlled maintenance study over 52 weeks, the frequency of herpes zoster in the upadacitinib 15 mg and 30 mg groups was 4.4% 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.
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 × 109 cells/L) associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease and atopic dermatitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.
In the placebo-controlled induction studies for up to 8 weeks, decreases in lymphocyte counts below 0.5 × 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 × 109 cells/L in at least one measurement occurred in 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 × 109 cells/L (see section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.
Elevations in lipid parameters were observed at 8 weeks of treatment with upadacitinib 45 mg and remained generally stable with longer-term treatment with upadacitinib 15 mg and 30 mg. Among patients in the placebo-controlled induction studies with baseline values below the specified limits, the following frequencies of patients were observed to shift to above the specified limits on at least one occasion during 8 weeks (including patients who had an isolated elevated value):
Overall, the safety profile observed in patients with Crohn’s disease treated with upadacitinib was consistent with the known safety profile for upadacitinib.
In the placebo-controlled induction studies, the frequency of serious infection over 12 weeks in the upadacitinib 45 mg group and the placebo group was 1.9% and 1.7%, respectively. In the placebo-controlled maintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and 30 mg groups was 3.2% and 5.7%, respectively, compared to 4.5% in the placebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups in patients who responded to upadacitinib 45 mg as induction treatment was 5.1 and 7.3 events per 100 patient-years, respectively. The most frequently reported serious infection in the induction and maintenance studies was gastrointestinal infections.
During the placebo-controlled period in the Phase 3 induction clinical studies, gastrointestinal perforation was reported in 1 patient (0.1%) treated with upadacitinib 45 mg and no patients on placebo through 12 weeks. In all patients treated with upadacitinib 45 mg (n=938) during the induction studies, gastrointestinal perforation was reported in 4 patients (0.4%).
In the long-term placebo-controlled period, gastrointestinal perforation was reported in 1 patient each treated with placebo (0.7 per 100 patient-years), upadacitinib 15 mg (0.4 per 100 patient-years), and upadacitinib 30 mg (0.4 per 100 patient-years). In all patients treated with rescue upadacitinib 30 mg (n=336), gastrointestinal perforation was reported in 3 patients (0.8 per 100 patient-years) through long-term treatment.
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 × 109 cells/L), and lipid parameters associated with upadacitinib treatment were generally similar to what was observed in the rheumatologic disease, atopic dermatitis and ulcerative colitis clinical studies. Dose-dependent changes for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.
In the placebo-controlled induction studies for up to 12 weeks, decreases in lymphocyte counts below 0.5 × 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 × 109 cells/L in at least one measurement occurred in 4.6%, 5.2% and 1.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to ALC <0.5 × 109 cells/L (see section 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinib treatment over time.
In the placebo-controlled induction studies for up to 12 weeks, decreases in haemoglobin concentration to below 8 g/dL in at least one measurement occurred in 2.7% and 1.4% of patients in the upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52 weeks, decreases in haemoglobin concentration below 8 g/dL in at least one measurement occurred in 1.4%, 4.4% and 2.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups, respectively. In clinical studies, treatment was interrupted in response to Hb <8 g/dL (see section 4.2). No notable mean changes of haemoglobin concentration were observed during upadacitinib treatment over time.
Based on limited data in atopic dermatitis 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.
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).
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 adolescents was similar to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated.
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.
Not applicable.
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