Serious Infections, Mortality, Malignancy, Major Adverse Cardiovascular Events (MACE), and Thrombosis

Serious Infections

• Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
• If a serious infection develops, interrupt XELJANZ until the infection is controlled.
• In the UC population, Tofacitinib Citrate treatment with 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with Tofacitinib Citrate 10 mg twice daily.

• Reported infections include:

               a. Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.

               b. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
               c. Bacterial, viral, and other infections due to opportunistic pathogens.

• The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
• Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Mortality

• Higher rate of all-cause mortality, including sudden cardiovascular death with XELJANZ vs. TNF blockers in rheumatoid arthritis (RA) patients.Higher rate of all-cause mortality, including sudden cardiovascular death with XELJANZ vs. TNF blockers in rheumatoid arthritis (RA) patients.
• Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 0.88 for XELJANZ 5 mg twice a day, 1.23 for XELJANZ 10 mg twice a day, and 0.69 for TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ.
• XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.
• For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Malignancies

• Malignancies have occurred in patients treated with XELJANZ. Higher rate of lymphomas and lung cancers with XELJANZ vs. TNF blockers in RA patients.
• Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus- associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

Major Adverse Cardiovascular Events (MACE) 

• Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with XELJANZ vs. TNF blockers in RA patients.

Thrombosis

• Thrombosis has occurred in patients treated with XELJANZ. Increased incidence of pulmonary embolism, venous and arterial thrombosis with XELJANZ vs. TNF blockers in RA patients. 
• Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, has been observed at an increased incidence in rheumatoid arthritis patients who were 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing safety study. Many of these events were serious and some resulted in death. Avoid XELJANZ/XELJANZ XR in patients at risk. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis.
• For patients with ulcerative colitis, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.