A 44-week, 2-part study (consisting of an 18-week, open-label, run-in phase, followed by a 26-week, double-blind, placebo-controlled, randomized withdrawal phase) in patients 2 to 17 years of age with active polyarthritis (including RF negative, RF positive, extended oligoarthritis, and systemic JIA without systemic manifestations for at least 6 weeks prior to screening) who had an IR or intolerance to at least one DMARD, which could have included MTX or biologic agents, and patients 2 to 17 years of age with jPsA and ERA who had an IR to NSAIDs.¹ A total of 225 patients (56 male and 169 female) were enrolled in the 18-week open-label run-in phase and received XELJANZ/XELJANZ Oral Solution dosed at 5 mg BID or body weight–based equivalent BID. Active polyarthritis patients enrolled in the run-in phase included RF negative (n=104) and RF positive (n=39) pcJIA, extended oligoarthritis (n=28), and systemic JIA without systemic manifestations (n=13), as well as jPsA (n=20) and ERA (n=21). Patients had a mean (SD) disease duration of 3.8±3.5 years, and a mean (SD) number of active joints of 12.2±8.1. Only patients who achieved at least a JIA ACR30 response at the end of the run-in phase (week 18) were randomized (1:1) to the double-blind phase. 173 patients (77%) met this criterion and were randomized into the double-blind phase to either XELJANZ/XELJANZ Oral Solution dosed at 5 mg BID (n=88) or body weight-based equivalent BID or placebo (n=85) for 26 weeks. Treatment with a stable dose of MTX was permitted but was not required during the study. Concurrent use of biologics or DMARDs other than MTX was not permitted in the study. In both the run-in and double-blind phases, approximately one-third of the patients were taking concomitant oral corticosteroids, and approximately two-thirds were taking concomitant MTX.¹ The primary endpoint was the occurrence of disease flare at week 44 relative to the double-blind phase baseline at week 18. Disease flare was defined as worsening of ≥30% in 3 or more of the 6 JIA core response variables with no more than 1 of the remaining JIA core response variables improving by ≥30% according to PRCSG/PRINTO Disease Flare criteria.¹

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 immunosupressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.
Reported infections include:

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

The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections.

In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.

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.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection.

In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers.

Lymphoma and lung cancers were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

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.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

Other malignancies were observed in clinical studies and the postmarketing 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. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.

RA patients 50 years of age and older with at least one cardiovascular (CV) risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients who are current or past smokers and patients with other CV risk factors. Inform patients about the symptoms of serious CV events. A XELJANZ 10 mg twice a day (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

Thrombosis, including pulmonary embolism, deep vein thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis.

A XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernible difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).

Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm³. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm³, treatment with XELJANZ is not recommended. 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. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm³) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm³. For patients who develop a persistent ANC of 500-1000 cells/mm³, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm³. In patients who develop an ANC less than 500 cells/mm³, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.