Please refer to the full PI for recommended dose modifications based on changes in lab tests.

• Prior to initiating XELJANZ it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines
• It is recommended that live vaccines not be given concurrently with XELJANZ. The decision to use live vaccines prior to XELJANZ treatment should take into account the pre-existing immunosuppression in a given patient
• Prophylactic zoster vaccination should be considered in accordance with vaccination guidelines. Particular consideration should be given to patients with long-standing rheumatoid arthritis who have received two or more prior biological DMARDs. If live zoster vaccine is administered, it should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus (VZV). If the history of chickenpox is considered doubtful or unreliable it is recommended to test for antibodies against VZV
• Vaccination with live vaccines should occur at least 2 weeks, but preferably 4 weeks prior to initiation of XELJANZ, or in accordance with current vaccination guidelines regarding immunomodulatory medicinal products

• Major adverse cardiovascular events (MACE) have been observed in patients taking tofacitinib.

• In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of myocardial infarctions was observed with tofacitinib compared to TNF inhibitors (see sections 4.8 and 5.1). In patients 65 years of age and older, patients who are current or past long-term smokers, and patients with other cardiovascular risk factors, tofacitinib should only be used if no suitable treatment alternatives are available.

• XELJANZ has not been studied and its use should be avoided in patients in combination with biologics such as TNF antagonists, IL-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL‑17 antagonists, IL‑12/IL‑23 antagonists, anti-integrins, and selective co-stimulation modulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection
• There is a higher incidence of adverse events for the combination of XELJANZ plus MTX versus XELJANZ as monotherapy in RA clinical trials

• Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The risk of opportunistic infections is higher in Asian geographic regions (see section 4.8 of the XELJANZ Summary of Product Characteristics). Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection.
• XELJANZ should not be initiated in patients with active infections, including localised infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients:
  • with recurrent infections,
  • with a history of a serious or an opportunistic infection,
  • who have resided or travelled in areas of endemic mycoses,
  • who have underlying conditions that may predispose them to infection,
  • who are 65 years of age and older.
• Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. Treatment must be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored
• 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 XELJANZ should only be considered if no suitable alternative treatment is available.
• Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are discussed in section 4.2 of the XELJANZ Summary of Product Characteristics.

• The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients:
  • who have been exposed to TB
  • who have resided or travelled in areas of endemic TB or endemic mycoses
• Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ

• Viral reactivation and cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. In patients treated with XELJANZ, the risk of herpes zoster appears to be increased in:
  • Japanese and Korean patients
  • Patients with an absolute lymphocyte count (ALC) less than 1.0 X10⁹ cells/L
  • Patients with long standing RA who have previously received two or more biologic DMARDs
  • Patients treated with 10 mg twice daily. 10mg twice daily dose is only licensed for UC patients

• XELJANZ should only be used in patients with other malignancy risk factors if no suitable treatment alternatives are available
• The risks and benefits of XELJANZ treatment should be considered prior to initiating therapy in patients with a current, or history of, malignancy other than successfully treated non-melanoma skin cancer (NMSC), or when considering continuing XELJANZ in patients who develop a malignancy. The possibility exists for XELJANZ to affect host defences against malignancies.
• Lymphomas have been observed in patients treated with XELJANZ. Patients with RA, particularly those with highly active disease may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. The role of XELJANZ in the development of lymphoma is uncertain.
• Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer and pancreatic cancer.
• The effect of XELJANZ on the development and course of malignancies is not known.

• Caution is recommended in patients with a history of chronic lung disease as they may be more prone to infections.
• Events of interstitial lung disease (some of which had a fatal outcome) have been reported in patients treated with XELJANZ in RA clinical trials and in the post-marketing setting although the role of Janus kinase (JAK) inhibition in these events is not known. Asian RA patients are known to be at higher risk of interstitial lung disease, thus caution should be exercised in treating these patients.

• Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients taking XELJANZ. A dose-dependent increased risk for VTE was observed in a clinical study with XELJANZ compared to TNF inhibitors.
• XELJANZ should be used with caution in patients with known risk factors for VTE, regardless of indication and dosage.
• VTE risk factors include previous VTE, patients undergoing major surgery, immobilisation, myocardial infarction (within previous 3 months), heart failure, use of combined hormonal contraceptives or hormone replacement therapy, inherited coagulation disorder, malignancy. Additional VTE, MACE and malignancy risk factors such as age, obesity (BMI ≥30), diabetes, hypertension, smoking status should also be considered. Patients should be re-evaluated periodically during XELJANZ treatment to assess for changes in VTE risk.
• Promptly evaluate patients with signs and symptoms of VTE and discontinue XELJANZ in patients with suspected VTE, regardless of dose or indication.
• XELJANZ should only be used in patients with other cardiovascular risk factors if no suitable treatment alternatives are available

• Retinal venous thrombosis (RVT) has been reported in patients treated with tofacitinib (see section 4.8 of the XELJANZ Summary of Product Characteristics). The patients should be advised to promptly seek medical care in case they experience symptoms suggestive of RVT.

• Increases in liver enzymes greater than 3x ULN were in general uncommonly reported, although they were more frequent in patients 50 years or older with at least one additional cardiovascular risk factor. Use caution with this population.
• Caution should be exercised when considering initiation of XELJANZ treatment in patients with elevated ALT or AST, particularly when initiated in combination with potentially hepatotoxic medicinal products such as MTX.
• Following initiation, routine monitoring of liver tests and prompt investigation of the causes of any observed liver enzyme elevations are recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.

• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia and anaemia.
• Recommendations for temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormailites.

• Treatment with XELJANZ was associated with increases in lipid parameters such as total cholesterol, LDL and HDL, maximum effects were generally observed within 6 weeks.
•  Assessment of lipid parameters should be performed 8 weeks after initiation of XELJANZ and managed according to hyperlipidaemia guidelines.

• Fractures have been observed in patients treated with tofacitinib. Tofacitinib should be used with caution in patients with known risk factors for fractures such as elderly patients, female patients and patients with corticosteroid use, regardless of indication and dosage.