XELJANZ / XELJANZ XR (tofacitinib) Warnings And Precautions

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WARNING: RISK OF SERIOUS INFECTIONS

Patients treated with XELJANZ/XELJANZ XR (tofacitinib) 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/XELJANZ XR 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/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use.
  • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized disease.
  • Bacterial, viral, and other infections due to opportunistic pathogens.

Treatment with XELJANZ/XELJANZ XR should not be initiated in patients with active infections including chronic or localized infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy (see ADVERSE REACTIONS).

MALIGNANCIES
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 (see WARNINGS AND PRECAUTIONS).

THROMBOSIS
Rheumatoid arthritis patients with at least one cardiovascular (CV) risk factor had a higher rate of all-cause mortalityand thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, with XELJANZ 10 mg twice daily compared to those treated with 5 mg twice daily or TNF blockers. Many of these adverse events were serious and some resulted in death. Avoid XELJANZ/XELJANZ XR in patients at risk of thrombosis. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis (see WARNINGS AND PRECAUTIONS, Cardiovascular).

For patients with ulcerative colitis (UC), use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response (see DOSAGE AND ADMINISTRATION).

General

Specific to XELJANZ XR :

As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). 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.

Cardiovascular

Heart Rate Decrease and PR Interval Prolongation: XELJANZ caused a decrease in heart rate and a prolongation of the PR interval (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, and ADVERSE REACTIONS). Caution should be observed in patients with a low heart rate at baseline (< 60 beats per minute), a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular (AV) block, ischemic heart disease, or congestive heart failure. Concomitant medications that result in a decrease in heart rate and/or PR interval prolongation should be avoided to the extent possible during treatment with XELJANZ/XELJANZ XR (see DRUG INTERACTIONS).

Thrombosis
Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, was observed at an increased incidence in patients treated with XELJANZ in a large, ongoing post-marketing study. Rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, and thrombosis compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers. Many of these events were serious and some resulted in death (see SERIOUS WARNINGS AND PRECAUTIONS BOX).

In a long-term extension study in patients with ulcerative colitis (UC), four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer.

A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or psoriatic arthritis (PsA) (see DOSAGE AND ADMINISTRATION).

For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response (see DOSAGE AND ADMINISTRATION).

Avoid XELJANZ/XELJANZ XR in patients that may be at increased risk of thrombosis. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis.”

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known. Many patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids. The relative contribution of these concomitant medications versus XELJANZ to the development of gastrointestinal perforations is not known.

There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with ulcerative colitis (UC), and many of them were receiving background corticosteroids.

XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., use of concomitant NSAIDs and/or corticosteroids, patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation (see ADVERSE REACTIONS).

Hepatic/Biliary/Pancreatic

XELJANZ/XELJANZ XR is contraindicated in patients with severe hepatic impairment.

Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo (see WARNINGS AND PRECAUTIONS – Laboratory parameters and ADVERSE REACTIONS).

Evaluate liver enzymes before initiating XELJANZ and thereafter according to routine patient management (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests). Prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury (DILI). If increases in ALT (alanine transaminase) or AST (aspartate transaminase) are observed and DILI is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until the diagnosis is excluded.

Most of the liver enzyme abnormalities in RA and PsA patients occurred in studies with background DMARD (primarily methotrexate) therapy.

One case of DILI was reported in a RA patient treated with tofacitinib 10 mg BID for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN associated concurrently with total bilirubin value greater than 2x ULN, which required hospitalization and a liver biopsy.

In UC patients, XELJANZ treatment with 5 and 10 mg BID was also associated with an increased incidence of liver enzyme elevation compared to placebo, with a trend for higher incidence with the 10 mg BID as compared to the 5 mg BID (see WARNINGS AND PRECAUTIONS – Laboratory parameters, and ADVERSE REACTIONS).

The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. XELJANZ/XELJANZ XR has not been studied in patients with positive hepatitis B virus or hepatitis C virus serology, and should therefore not be used in these populations.

XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment, and should not be used in these patients. XELJANZ XR should not be used in patients with moderate to severe hepatic impairment Dose adjustment of XELJANZ is recommended for patients with moderate hepatic impairment (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Immune

Hypersensitivity Reactions: Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients treated with XELJANZ/XELJANZ XR. Some events were serious. If a hypersensitivity reaction is suspected, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction (see CONTRAINDICATIONS and ADVERSE REACTIONS).

Immunocompromised Patients: XELJANZ/XELJANZ XR can increase the risk of infections and immunosuppression when co-administered with potent immunosuppressants such as cyclosporine, azathioprine and tacrolimus. Combined use of XELJANZ/XELJANZ XR with potent immunosuppressive drugs has not been studied and is not recommended (see DRUG INTERACTIONS).

Immunizations

No data are available on the secondary transmission of infection by live vaccines to patients receiving XELJANZ/XELJANZ XR. It is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy and that live vaccines not be given concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunomodulatory agents.

In patients being considered for XELJANZ/XELJANZ XR therapy, live zoster vaccine should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus. Vaccination should occur at least 2 weeks but preferably 4 weeks before initiating immunomodulatory agents such as XELJANZ/XELJANZ XR.

In a clinical trial, a varicella naïve patient treated with XELJANZ and methotrexate developed disseminated infection with the vaccine strain of the varicella zoster virus 16 days after vaccination. A satisfactory immune response to the vaccine was developed 6 weeks post-vaccination.

In a randomized, double-blind, placebo-controlled study in 200 adult RA patients treated with XELJANZ 10 mg BID or placebo, humoral responses to concomitant pneumococcal and influenza vaccines were assessed. The percentages of patients achieving a satisfactory humoral response to pneumococcal vaccines were lower for the XELJANZ group than the placebo group. This effect was more pronounced for patients receiving background methotrexate. A total of 31.6% XELJANZ-treated subjects and 61.8% placebo-treated subjects who received background methotrexate achieved a ≥ 2-fold increase in antibody concentrations to ≥ 6 of 12 pneumococcal antigens.

In the same study, the proportion of patients achieving protective antibody levels to the influenza antigens was lower in the XELJANZ group (64.9%) compared to the placebo group (92.7%) in patients receiving background methotrexate. However, the difference in humoral response to the influenza vaccine was small with 50.9% of patients in the XELJANZ group and 58.2% in the placebo group with background methotrexate achieving a ≥ 4-fold increase in antibody titers to ≥ 2 of 3 influenza antigens.

Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving immunomodulatory agents, including biologic DMARDs and XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infections, and listeriosis were reported with XELJANZ (see ADVERSE REACTIONS). Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

Patients treated with XELJANZ 10 mg BID are at higher risk of serious infections, and herpes zoster infections compared to those treated with 5 mg BID. The incidence rate per 100 person-years (PYs) for herpes zoster opportunistic infections in the UC 52 week maintenance study was higher in patients treated with XELJANZ 10 mg BID (6.64) as compared to XELJANZ 5 mg BID (2.05) or placebo (0.97).(see ADVERSE REACTIONS)

XELJANZ/XELJANZ XR should not be administered in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ/XELJANZ XR in patients:

  • with chronic or recurrent infections,
  • who have been exposed to tuberculosis,
  • with a history of a serious or an opportunistic infection,
  • who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or
  • with 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/XELJANZ XR. XELJANZ/XELJANZ XR 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/XELJANZ XR 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. Caution is also 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 RA patients treated with XELJANZ in clinical trials and in the post-marketing setting.

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.

For discontinuation and monitoring criteria for lymphopenia see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests.

Treatment with XELJANZ was associated with increased rates of infections in Asian patients compared to other races (see WARNINGS AND PRECAUTIONS – Special Populations and ADVERSE REACTIONS). XELJANZ/XELJANZ XR should be used with caution in this population.

Tuberculosis
Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ/XELJANZ XR and periodically (e.g. annually) while taking XELJANZ/XELJANZ XR.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Antituberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but have risk factors for tuberculosis infection.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR.

Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. Post-marketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ (see ADVERSE REACTIONS). The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who 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/XELJANZ XR.

Laboratory Parameters

Lymphopenia: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, XELJANZ/XELJANZ XR should be discontinued.

For recommended monitoring and dose modifications based on lymphocyte counts see WARNINGS AND PRECAUTIONSMonitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (<2000/mm3) compared to placebo.

Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC (absolute neutrophil count) <1000/mm3). For patients who develop a persistent ANC of 500-1000/mm3, interrupt dosing until ANC is >1000 cells/mm3. In patients who develop an absolute neutrophil count <500 cells/mm3, discontinue treatment. For recommended monitoring and dose modification based on ANC, see WARNINGS AND PRECAUTIONSMonitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION.

Anemia: Treatment with tofacitinib has been associated with decreases in hemoglobin levels. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with low hemoglobin values (i.e., <9 g/dL). Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels <8 g/dL or whose hemoglobin level drops >2 g/dL on treatment.

For recommended monitoring and dose modification based on hemoglobin results, see WARNINGS AND PRECAUTIONSMonitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo (see WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic, and ADVERSE REACTIONS). Most of these abnormalities in RA and PsA patients occurred in studies with background DMARD (primarily methotrexate) therapy.

In UC patients, XELJANZ treatment with 5 and 10 mg BID was also associated with an increased incidence of liver enzyme elevation compared to placebo, with a trend for higher incidence with the 10 mg BID dose as compared to the 5 mg BID dose.

One patient treated with XELJANZ 10 mg BID in the maintenance UC study experienced an increase in liver enzymes which decreased upon discontinuation of treatment. The case was adjudicated as possible DILI, while noting ultrasound findings of fatty liver.

Routine monitoring of liver enzymes and prompt investigation of the cause of liver enzyme elevations is recommended to identify potential cases of DILI (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests).

Lipid Elevations: Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see ADVERSE REACTIONS).

Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assessment of lipid parameters should be performed at baseline and approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy, and every 6 months thereafter (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests). Patients should be managed according to local clinical guidelines for the management of hyperlipidemia.

Malignancies and Lymphoproliferative Disorder

Malignancies have been observed in patients treated with XELJANZ. In patients treated with XELJANZ, malignancies were observed in clinical studies and the post marketing setting including but not limited to: lymphomas, lung cancer, breast cancer, colorectal cancer, gastric cancer, melanoma, prostate cancer, pancreatic cancer and renal cell carcinoma.

Consider the risks and benefits of XELJANZ/XELJANZ XR treatment 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/XELJANZ XR in patients who develop a malignancy. Recommendations for non-melanoma skin cancer are presented below.

Rheumatoid Arthritis

In the 5 controlled clinical studies, 5- malignancies (excluding non-melanoma skin cancers (NMSC)) were diagnosed in patients receiving XELJANZ 5 mg BID, and 8 malignancies (excluding NMSC) were diagnosed in patients receiving XELJANZ 10 mg BID, compared to 0 malignancies (excluding NMSC) in patients in the placebo/placebo plus DMARD group during the first 12 months. Lymphomas and solid cancers have also been observed in the long-term extension study in patients treated with XELJANZ (see ADVERSE REACTIONS). Patients with RA particularly those with highly active disease, may be at a higher risk (several fold) than the general population for the development of lymphoma.

In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Psoriatic Arthritis

In the 2 controlled PsA clinical trials, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus csDMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus csDMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus csDMARD group (12 months exposure). Malignancies have also been observed in the long‑term extension study in PsA patients treated with XELJANZ.

Ulcerative Colitis

In the 4 controlled clinical studies for ulcerative colitis (up to 52 week treatment), no malignancies (excluding NMSC) were reported with XELJANZ. In the long-term extension open-label study, malignancies (excluding NMSC) have been observed in patients treated with XELJANZ 10 mg BID, including solid cancers and lymphoma.

Non Melanoma Skin Cancer

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ.
NMSC is a dose related adverse reaction, with a greater risk in patients treated with 10 mg BID of XELJANZ than in patients treated with 5 mg BID. Periodic skin examination is recommended.

In the UC 52 week maintenance study, NMSC was reported in 3 patients (1.5%) treated with 10 mg BID, as compared with no reported events in patients treated with 5 mg BID and 1 patient (0.5%) treated with placebo. In the long-term open label extension study, NMSC was reported in 6 patients in the 10 mg BID group and 2 patients in the 5 mg BID group.

Monitoring and Laboratory Tests

Lipid tests should be performed at baseline, approximately 4-8 weeks after initiation with XELJANZ/XELJANZ XR and every 6 months thereafter.

Liver enzymes tests are recommended. If DILI is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded.

Assessment of renal function is recommended prior to initiation of XELJANZ/XELJANZ XR (see DOSAGE AND ADMINISTRATION).

Lymphocyte, neutrophil and hemoglobin tests should be performed at baseline, approximately 4-8 weeks after initiation with XELJANZ/XELJANZ XR treatment, and every 3 months thereafter (see DOSAGE AND ADMINISTRATION for recommended dose adjustment based on these laboratory tests).

Vital signs: Patients should be monitored for pulse rate and blood pressure at baseline and periodically during treatment with XELJANZ/XELJANZ XR (see WARNINGS AND PRECAUTIONSCardiovascular, ADVERSE REACTIONS, and DRUG INTERACTIONS).

Musculoskeletal

Treatment with XELJANZ was associated with increases in creatine kinase (CK). Maximum effects were generally observed within 6 months. Rhabdomyolysis was reported in one patient treated with XELJANZ. Creatine kinase levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis. Increases in CK were reported more frequently in patients treated with XELJANZ 10 mg as compared to those treated with 5 mg BID (see ADVERSE REACTIONS).

Renal

XELJANZ XR is not recommended in patients with moderate (CLcr ≥30 and <60 mL/min), or severe renal insufficiency (CLcr ≥15 and <30 mL/min), including patients with end-stage renal disease (ESRD) but not limited to those undergoing hemodialysis.

Dosage adjustment of XELJANZ is recommended in patients with moderate and severe renal impairment (see WARNINGS AND PRECAUTIONS – Special Populations, DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY). In clinical trials, XELJANZ was not evaluated in patients with baseline creatinine clearance values (estimated by the Cockcroft-Gault equation) less than 40 mL/min.

Respiratory

Interstitial Lung Disease: Events of interstitial lung disease (ILD) have been reported in RA clinical trials with XELJANZ, although the role of JAK inhibition in these events is not known. All patients who developed ILD were taking concomitant methotrexate, corticosteroids and/or sulfasalazine, which have been associated with ILD. Asian patients had an increased risk of ILD (see WARNINGS AND PRECAUTIONS – Special Populations).

XELJANZ/XELJANZ XR should be used with caution in patients with a risk or history of ILD.

Special Populations

Pregnant Women : XELJANZ/XELJANZ XR is contraindicated during pregnancy (see CONTRAINDICATIONS). There are no adequate and well-controlled studies on the use of XELJANZ/XELJANZ XR in pregnant women. XELJANZ has been shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility, parturition, and peri/postnatal development. (see TOXICOLOGY).

Women of reproductive potential should be advised to use effective contraception during XELJANZ/XELJANZ XR treatment and for 4 to 6 weeks after the last dose.

Nursing Women : XELJANZ was secreted in milk of lactating rats. It is not known whether XELJANZ/XELJANZ XR is excreted in human milk. XELJANZ/XELJANZ XR is contraindicated in women who breastfeed (see CONTRAINDICATIONS and TOXICOLOGY).

Pediatrics (<18 years of age) : The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established. Therefore XELJANZ/XELJANZ XR should not be used in this patient population (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Geriatrics (>65 years of age) : The frequency of serious infection among XELJANZ treated subjects 65 years of age and older was higher than among those under the age of 65. Caution should be used when treating the elderly with XELJANZ/XELJANZ XR (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Asian Patients : Asian patients have an increased risk of herpes zoster and opportunistic infections. Asian patients with RA also have an increased risk of interstitial lung disease. An increased incidence of some adverse events such as elevated transaminases (ALT, AST) and decreased white blood cells (WBCs) were also observed. Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients (see ADVERSE REACTIONS).