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 or inactivated 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.
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.
Malignancies were observed in clinical studies of upadacitinib. 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 non-melanoma skin cancer (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).
Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients treated with upadacitinib should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care.
Lipids: Treatment with upadacitinib was associated with 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. 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.
Effects on ability to drive and use machines: Upadacitinib has no or negligible influence on the ability to drive and use machines.