Important Safety InformationSERIOUS INFECTIONS
Patients treated with XELJANZ* are at increased risk for developing serious bacterial, fungal, viral, and opportunistic infections, including tuberculosis (TB) that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.
Reported infections include:
- Active TB, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent TB 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 XELJANZ treatment 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. Perform screening for viral hepatitis 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 XELJANZ treatment, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. If a serious infection develops, interrupt XELJANZ until the infection is controlled.
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.
MORTALITY
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 or 10mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ tablets 5 mg or 10mg twice a day. XELJANZ 10 mg twice daily and XELJANZ XR 22 mg once daily dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. MALIGNANCIES
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 non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ tablets 5 mg or 10mg twice a day compared with TNF blockers.
Lymphoma and lung cancers were observed at a higher rate in patients treated with XELJANZ tablets 5 mg or 10mg 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.
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.
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. XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA.
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. MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)
RA patients 50 years of age and older with at least one CV risk factor, treated with XELJANZ tablets 5 mg or 10mg 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. XELJANZ 10 mg twice a day (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA.
THROMBOSIS
Thrombosis, including pulmonary embolism, deep venous 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 CV risk factor treated with XELJANZ tablets 5 mg or 10mg 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.
XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA. 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
Gastrointestinal (GI) perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with RA were receiving background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). There was no discernible difference in frequency of GI perforation between the placebo and the XELJANZ treatment groups in clinical trials of patients with UC, and many of them were receiving background corticosteroids. Promptly evaluate patients treated with XELJANZ who may be at increased risk for GI perforation (e.g., patients with a history of diverticulitis or taking NSAIDs) and who present with new onset abdominal symptoms for early identification of GI perforation.
HYPERSENSITIVITY REACTIONS
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.
LABORATORY ABNORMALITIES
Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Monitor lymphocyte counts at baseline and every 3 months thereafter. 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.
Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to treatment with placebo. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. 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.
Anemia: Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Interrupt treatment with XELJANZ in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.
Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to treatment with placebo. Most of these abnormalities occurred in studies with background DMARD therapy (primarily methotrexate). If drug-induced liver injury is suspected, interrupt the administration of XELJANZ 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 changes in these lipid parameters 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. Perform assessment of lipid parameters approximately 4-8 weeks following initiation of XELJANZ therapy. VACCINATIONS
Avoid use of live vaccines concurrently with XELJANZ. Prior to initiating XELJANZ therapy, update immunizations in agreement with current immunization guidelines. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. RISK OF GI OBSTRUCTION WITH XELJANZ XR
XELJANZ XR is a non-deformable extended release formulation. GI obstruction may occur with XELJANZ XR. Avoid use of XELJANZ XR in patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended-release formulation. HEPATIC and RENAL IMPAIRMENT
Use of XELJANZ in patients with severe hepatic impairment is not recommended. For patients with moderate hepatic impairment or with moderate or severe renal impairment the recommended dosage of XELJANZ is lower than the dosage recommended for patients with normal hepatic or renal function. ADVERSE REACTIONS
The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in adult patients with RA with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA.
Adverse reactions reported in ≥5% of patients treated with either XELJANZ 5 mg or 10 mg twice daily and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials of patients with UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.
USE IN PREGNANCY
Available data with XELJANZ use in pregnant women are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.
*Unless otherwise stated, “XELJANZ” in the Important Safety Information refers to XELJANZ, XELJANZ XR, and XELJANZ Oral Solution.
Please see full Prescribing Information, including BOXED WARNING and Medication Guide.
IndicationRheumatoid Arthritis
XELJANZ and XELJANZ XR (tofacitinib) are indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ or XELJANZ XR in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Psoriatic Arthritis
XELJANZ (tofacitinib) is indicated for the treatment of adult and pediatric patients 2 years of age and older with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers.
XELJANZ XR is indicated for the treatment of adults with active PsA who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ or XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Ankylosing Spondylitis
XELJANZ or XELJANZ XR are indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ or XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended
Polyarticular Course Juvenile Idiopathic Arthritis
XELJANZ is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Ulcerative Colitis
XELJANZ or XELJANZ XR (tofacitinib) are indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers.
Limitations of Use: Use of XELJANZ or XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 
