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Immunosuppressive medicinal products: Combination with other potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.
Serious infections: Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported with upadacitinib included pneumonia and cellulitis (see Adverse Reactions). Cases of bacterial meningitis and sepsis have been reported in patients receiving upadacitinib. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis were reported with upadacitinib.
Upadacitinib should not be initiated in patients with an active, serious infection, including localised infections.
Consider the risks and benefits of treatment prior to initiating upadacitinib in patients: with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of a serious or an opportunistic infection; who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with upadacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and upadacitinib therapy should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib therapy may be resumed once the infection is controlled.
A higher rate of serious infections was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients 65 years of age and older, upadacitinib should only be used if no suitable treatment alternatives are available (see Dosage & Administration).
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 Japanese patients treated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves.
Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted.
Vaccination: No data are available on the response to vaccination with live vaccines in patients receiving upadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended. Prior to initiating upadacitinib treatment, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines (see Pharmacology: Pharmacodynamics under Actions for data on adjuvanted recombinant glycoprotein E herpes zoster vaccine and inactivated pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) and concomitant use with upadacitinib).
Malignancy: Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including upadacitinib.
In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.
A higher rate of malignancies was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.
In patients 65 years of age and older, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g., current malignancy or history of malignancy) upadacitinib should only be used if no suitable treatment alternatives are available.
Non-melanoma skin cancer: NMSCs have been reported in patients treated with upadacitinib (see Adverse Reactions). A higher rate of NMSC was observed with upadacitinib 30 mg compared to upadacitinib 15 mg. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Haematological abnormalities: Absolute Neutrophil Count (ANC) <1 x 109 cells/L, Absolute Lymphocyte Count (ALC) <0.5 x 109 cells/L and haemoglobin <8 g/dL were reported in ≤1% of patients in clinical trials (see 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).
Gastrointestinal perforations: Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and from post-marketing sources (see Adverse Reactions).
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.
Major adverse cardiovascular events: Events of MACE were observed in clinical studies of upadacitinib.
In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors.
Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, upadacitinib should only be used if no suitable treatment alternatives are available.
Lipids: Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see 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) 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 "Major adverse cardiovascular events" and "Malignancy" as previously mentioned) 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.
Hypersensitivity reactions: Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients receiving upadacitinib. If a clinically significant hypersensitivity reaction occurs, discontinue upadacitinib and institute appropriate therapy (see Contraindications and Adverse Reactions).
Effects on ability to drive and use machines: Upadacitinib has no or negligible influence on the ability to drive and use machines.
Use in the Elderly: 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 Dosage & Administration and Adverse Reactions).
