Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.
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.
Carcinogenesis and Mutagenesis
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, thyroid cancer and renal cell carcinoma (see 3 SERIOUS WARNINGS AND PRECAUTIONS and 8.2 Clinical Trial Adverse Reactions).
An increase in malignancies (excluding NMSC) was observed in patients treated with XELJANZ compared with TNF inhibitors in a post-authorization safety study (see 8.2 Clinical Trial Adverse Reactions). Malignancies (excluding NMSC) were more common in geriatric patients and in patients who were current or past smokers.
Lung cancers were observed in patients treated with XELJANZ and an increased rate was observed in patients treated with XELJANZ 10 mg BID compared with TNF inhibitors in a post-authorization safety study. Patients with rheumatoid arthritis and taking tofacitinib may be at higher risk than the general population for the development of lung cancer.
Lymphomas were also observed in patients treated with XELJANZ in a post-authorization safety study (see 8.2 Clinical Trial Adverse Reactions).
Caution should be used in treating geriatric patients, patients who are current or past smokers, and patients with other malignancy risk factors.
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 NMSC are presented below.
Rheumatoid Arthritis
In the 5 controlled clinical studies, 5 malignancies (excluding 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 8.2 Clinical Trial 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 DMARD 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. An increase in overall NMSCs, including cutaneous squamous cell carcinomas was observed in patients treated with XELJANZ compared to TNF inhibitors in a post-authorization safety study (see 8.2 Clinical Trial Adverse Reactions). Caution should be used when treating geriatric patients and patients with a prior history of NMSC, where a higher incident of NMSC was observed. 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.
Cardiovascular
Heart Rate Decrease and PR Interval Prolongation: XELJANZ caused a decrease in heart rate and a prolongation of the PR interval (see 7 WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests and 8 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 9 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 post-authorization safety study. In this post-authorization safety study, patients treated with XELJANZ 10 mg BID had a higher rate of all-cause mortality, including sudden CV death, and thrombosis compared to those treated with XELJANZ 5 mg given BID or TNF inhibitors. Many of these events were serious and some resulted in death (see 3 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 BID, including one death in a patient with advanced cancer.
A dosage of XELJANZ 10 mg BID or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA (see 4 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 4 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.
Major Adverse Cardiovascular Events (including Myocardial Infarction)
Major adverse cardiovascular events (MACE), including events of myocardial infarction, were observed in patients were treated with XELJANZ 5 mg BID, XELJANZ 10 mg BID or TNF inhibitors in a post-authorization safety study. An increase in non-fatal myocardial infarctions was observed in patients treated with tofacitinib compared to TNF inhibitor (see 8.2 Clinical Trial Adverse Reactions). MACE, including events of myocardial infarction, were more common in geriatric patients and in patients who were current or past smokers (see 3 SERIOUS WARNINGS AND PRECAUTIONS). Caution should be used in treating geriatric patients, patients who are current or past smokers, and patients with other CV risk factors.
Driving and Operating Machinery
No formal studies have been conducted on the effects on the ability to drive and use machines.
Fractures
Fractures of multiple types, including osteoporotic fractures, have been observed in patients treated with XELJANZ/XELJANZ XR in clinical studies and the postmarketing setting (see 8.2 Clinical Trial ADVERSE REACTIONS Adverse Reactions).
Caution should be applied when using XELJANZ/XELJANZ XR in patients with known risk factors for fractures such as geriatric patients, female patients, and patients using corticosteroids.
Gastrointestinal
Events of gastrointestinal perforation have been reported with XELJANZ in RA patients, in clinical trials and in the post-market setting. 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 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 8 ADVERSE REACTIONS).
Hematologic
Anemia: Treatment with XELJANZ/XELJANZ XR has been associated with decreases in hemoglobin levels. Evaluate hemoglobin prior to initiation of XELJANZ/XELJANZ XR (see 7 WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests and 4.2 Recommended Dose and Dosage Adjustment). Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with low hemoglobin values (i.e., <90 g/L). Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels <80 g/L or whose hemoglobin level drops >20 g/L on treatment.
For recommended monitoring and dose modification based on hemoglobin results, see 7 WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests and 4.2 Recommended Dose and Dosage Adjustment.
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 0.5 x 109 cells/L were associated with an increased incidence of treated and serious infections. Evaluate lymphocyte count prior to initiation of XELJANZ/XELJANZ XR approximately 4-8 weeks after initiation with XELJANZ/XELJANZ XR treatment, and every 3 months thereafter.
Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 0.5 x 109cells/L). In patients who develop a confirmed absolute lymphocyte count less than 0.5 x 109cells/L, XELJANZ/XELJANZ XR should be discontinued.
For recommended monitoring and dose modifications based on lymphocyte counts see 7 WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests and 4.2 Recommended Dose and Dosage Adjustment.
Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (<2 x 109 cells/L) compared to placebo. Evaluate neutrophil count prior to initiation of XELJANZ/XELJANZ XR approximately 4-8 weeks after initiation with XELJANZ/XELJANZ XR treatment, and every 3 months thereafter.
Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC (absolute neutrophil count) <1 x 109cells/L). For patients who develop a persistent ANC of 0.5 to 1 x 109 cells/L, interrupt dosing until ANC is >1 x 109cells/L. In patients who develop an absolute neutrophil count <0.5 x 109 cells/L, discontinue treatment.
For recommended monitoring and dose modification based on ANC, see 7 WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests and 4.2 Recommended Dose and Dosage Adjustment.
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 8 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 7 WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests). Patients should be managed according to local clinical guidelines for the management of hyperlipidemia.
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 8 ADVERSE REACTIONS).
Evaluate liver enzymes before initiating XELJANZ and thereafter according to routine patient management (see 7 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 with values 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 8 ADVERSE REACTIONS).
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.
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 4 DOSAGE AND ADMINISTRATION and 10 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 2 CONTRAINDICATIONS and 8 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 9.4 Drug-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.
Antibody levels after vaccination may be lower in patients treated with XELJANZ (see 10.2 Pharmacodynamics)
Infections: Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in RA patients receiving immunomodulatory agents, including XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, urinary tract infection, cellulitis, herpes zoster, bronchitis, septic shock, diverticulitis, gastroenteritis, appendicitis and sepsis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infections, listeriosis and aspergillosis were reported with XELJANZ (see 8 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).
A dose dependent increase in serious infections was observed in patients treated with XELJANZ compared to TNF inhibitors in a post-authorization safety study (see 8 ADVERSE REACTIONS). Some of these serious infections resulted in death. Opportunistic infections were also reported in the study.
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 8 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 geriatric and in the diabetic populations in general, caution should be used when treating geriatric patients 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 (see 7 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 7.1.5 Asian Patients and 8 ADVERSE REACTIONS). XELJANZ/XELJANZ XR should be used with caution in this population.
Tuberculosis
Patients should be evaluated and tested for latent or active tuberculosis (TB) infection prior to administration of XELJANZ/XELJANZ XR and periodically (e.g., annually) while taking XELJANZ/XELJANZ XR.
XELJANZ/XELJANZ XR should not be given to patients with active TB.
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.
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.
Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. An increase in herpes zoster events was observed in patients treated with XELJANZ compared to TNF inhibitors in a post-authorization safety study (see 8 ADVERSE REACTIONS). Post-marketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ (see 8 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.
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. Patients should be managed according to clinical guidelines for the management of hyperlipidemia (see 4.2 Recommended Dose and Dosage Adjustment and 7 WARNINGS AND PRECAUTIONS).
Liver enzyme tests are recommended before initiating XELJANZ/XELJANZ XR treatment and thereafter according to routine patient management. If increases in ALT or AST are observed during routine patient management and DILI is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded (see 4.2 Recommended Dose and Dosage Adjustment and 7 WARNINGS AND PRECAUTIONS).
Assessment of renal function is recommended prior to initiation of XELJANZ/XELJANZ XR (see 4.2 Recommended Dose and Dosage Adjustment and 7 WARNINGS AND PRECAUTIONS).
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 4.2 Recommended Dose and Dosage Adjustment and 7 WARNINGS AND PRECAUTIONS).
Vital signs: Patients should be monitored for pulse rate and blood pressure at baseline and periodically during treatment with XELJANZ/XELJANZ XR (see 7 WARNINGS AND PRECAUTIONS – Cardiovascular, 8 ADVERSE REACTIONS, and 9.4 Drug-Drug Interactions 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 8 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, 4.2 Recommended Dose and Dosage Adjustment, and 10 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.
Reproductive Health: Female and Male Potential
- Fertility: Based on findings in animal studies, XELJANZ/ XELJANZ XR may cause decreased fertility when administered to females (see 16 NON-CLINICAL TOXICOLOGY).
- Teratogenic Risk: Based on findings in animal studies, XELJANZ/ XELJANZ XR may cause fetal harm when administered to a pregnant woman (see 2 CONTRAINDICATIONS). Administration of tofacitinib to rats and rabbits during organogenesis caused increases in fetal malformations (see 16 NON-CLINICAL TOXICOLOGY). Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with XELJANZ/ XELJANZ XR and for 4 to 6 weeks following completion of therapy (see 7.1.1 Pregnant Women).
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 7.1.5 Asian Patients).
XELJANZ/XELJANZ XR should be used with caution in patients with a risk or history of ILD.
7.1 Special Populations
7.1.1 Pregnant Women
XELJANZ/XELJANZ XR is contraindicated during pregnancy (see 2 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 16 NON-CLINICAL 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.
7.1.2 Breast-feeding
XELJANZ/XELJANZ XR is contraindicated in women who breastfeed (see 2 CONTRAINDICATIONS). XELJANZ was secreted in milk of lactating rats. It is not known whether XELJANZ/XELJANZ XR is excreted in human milk. (see 16 NON-CLINICAL TOXICOLOGY).
7.1.3 Pediatrics
Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada
has not authorized an indication for pediatric use.
7.1.4 Geriatrics
Geriatrics (>65 years of age): The frequency of adverse events including serious infections, all-cause mortality, cardiovascular events, malignancies, non-melanoma skin cancer, gastrointestinal perforations, interstitial lung disease, venous thromboembolism, and arterial thromboembolism 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 geriatric patients with XELJANZ/XELJANZ XR (see 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY).
7.1.5 Asian Patients
Asian patients have an increased risk of herpes zoster and opportunistic infections. Asian patients with RA also have an increased risk of ILD. 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 8 ADVERSE REACTIONS).