XELJANZ^® (tofacitinib) has not been studied and its use should be avoided in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monocional antibodies, IL-1 antagonists, IL-12/IL-23 antagonists, antiintegrins, 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.

The use of XELJANZ^® (tofacitinib) in combination with phosphodiesterase 4 inhibitors has not been studied in tofacitinib clinical studies.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ^® (tofacitinib). Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection.

XELJANZ^® (tofacitinib) 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^® (tofacitinib) 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

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ^® (tofacitinib). Treatment should 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^® (tofacitinib) 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. 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 available.

The risks and benefits of treatment should be considered prior to initiating XELJANZ^® (tofacitinib) in patients:

• who have been exposed to TB
• who have resided or travelled in areas of endemic TB

Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ^® (tofacitinib).

Patients with latent TB, who test positive, should be treated with standard antimycobacterial therapy before administering XELJANZ^® (tofacitinib).

Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ^® (tofacitinib) in patients who test negative for TB but who have a past history of latent or active TB and where an adequate course of treatment cannot be confirmed; or those who test negative but who have risk factors for TB infection.

Consultation with a healthcare professional with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely 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 and cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ^® (tofacitinib). In patients treated with XELJANZ^® (tofacitinib), the incidence of herpes zoster appears to be increased in:

• Patients with an ALC less than 1 000 cells/mm3
• Patients with longstanding RA who have previously received two or more biological disease modifying antirheumatic drugs (DMARDs)
• Patients treated with 10 mg twice daily

The impact of XELJANZ^® (tofacitinib) on chronic viral hepatitis reactivation is unknown. Patients screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ^® (tofacitinib).

The risks and benefits of XELJANZ^® (tofacitinib) treatment should be considered prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ^® (tofacitinib) in patients who develop a malignancy. The possibility exists for XELJANZ^® (tofacitinib) to affect host defences against malignancies.

Lymphomas have been observed in patients treated with XELJANZ^® (tofacitinib). The effect of XELJANZ^® (tofacitinib) on 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.

NMSCs have been reported in patients treated with XELJANZ^® (tofacitinib). The risk of NMSC may be higher in patients treated with XELJANZ^® (tofacitinib) 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Pulmonary embolism (PE) has been observed in patients taking XELJANZ^® (tofacitinib) in clinical trials and post-marketing reports. XELJANZ^® (tofacitinib) 10 mg twice daily is contraindicated in patients who are at high risk for pulmonary embolism. Additional risk factors that should be considered in determining the patient’s risk for PE are older age, obesity, smoking status, and immobilisation.

Caution is also recommended in patients with a history of chronic lung disease as they may be more prone to infections.

Events of gastrointestinal perforation have been reported in clinical trials although the role of JAK inhibition in these events is not known. XELJANZ^® (tofacitinib) should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e. g., patients with a history of diverticulitis, patients with concomitant use of corticosteroids and/or nonsteroidal anti-inflammatory drugs). Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

PsA patients have an increased risk for cardiovascular disorders. Patients treated with XELJANZ^® (tofacitinib) should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care.

Treatment with XELJANZ^® (tofacitinib) was associated with an increased incidence of liver enzyme elevation in some patients. Caution should be exercised when considering initiation of XELJANZ^® (tofacitinib) treatment in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), particularly when initiated in combination with potentially hepatotoxic medicines 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^® (tofacitinib) should be interrupted until this diagnosis has been excluded.

In post-marketing experience, cases of medicine hypersensitivity associated with XELJANZ^® (tofacitinib) administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, XELJANZ^® (tofacitinib) should be discontinued immediately.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. There is no specific antidote for overdose with XELJANZ^® (tofacitinib). Treatment should be symptomatic and supportive.

Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95 % of the administered dose is expected to be eliminated within 24 hours.

XELJANZ^® (tofacitinib) has no or negligible influence on the ability to drive and use machines.