XELJANZ / XELJANZ XR 9 Drug Interactions

Rheumatoid Arthritis

XELJANZ/XELJANZ XR (tofacitinib), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms of rheumatoid arthritis (RA) in adult patients with moderately to severely active RA who have had an inadequate response to MTX and to one or more disease-modifying anti-rheumatic drugs (DMARDs).

In cases of intolerance to MTX and other DMARDs, physicians may consider the use of XELJANZ/XELJANZ XR (tofacitinib) as monotherapy.

Psoriatic Arthritis

XELJANZ (tofacitinib), in combination with methotrexate (MTX) or another conventional synthetic disease-modifying antirheumatic drug (DMARD), is indicated for reducing the signs and symptoms of psoriatic arthritis (PsA) in adult patients with active PsA when the response to previous DMARD therapy has been inadequate.

Ankylosing Spondylitis

XELJANZ (tofacitinib) is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have responded inadequately to a biologic DMARD or when use of those therapies is inadvisable.

Ulcerative Colitis

XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) with an inadequate response, loss of response or intolerance to either conventional UC therapy or a TNFα inhibitor.

Limitations of Use

XELJANZ should not be used in combination other Janus kinase (JAK) inhibitors, immunomodulating biologics (e.g., biologic DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine.

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. 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 in XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. Therefore, caution should be used when treating geriatric patients with XELJANZ/XELJANZ XR (see 7 WARNINGS AND PRECAUTIONS, 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY).

XELJANZ/XELJANZ XR (tofacitinib) is contraindicated:

• In patients with known hypersensitivity to tofacitinib or ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• In patients with severe hepatic impairment (see 7 WARNINGS AND PRECAUTIONS).
• During pregnancy and breastfeeding (see 1.1 Pregnancy and 7.1.2 Breast-feeding).

4.1 Dosing Considerations

• Use of XELJANZ/XELJANZ XR with other potent systemic immunosuppressants should be avoided. Combined use of XELJANZ/XELJANZ XR with potent immunosuppressants or biologic DMARDS (tumor necrosis factor (TNF) antagonists, interleukin 1 receptor (IL-1R) antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL‑17 antagonists, IL‑12/IL‑23 antagonists and selective co-stimulation modulators) has not been studied in RA, PsA and UC patients. There is a risk of added immunosuppression when XELJANZ/XELJANZ XR is coadministered with potent immunosuppressive drugs (e.g. azathioprine, tacrolimus, cyclosporine). 

• XELJANZ/XELJANZ XR should not be initiated in patients with an absolute neutrophil count (ANC) less than 1 x 10⁹ cells/L, hemoglobin (Hgb) levels <90 g/L, or with a lymphocyte count less than 0.5 x 10⁹ cells/L (see 7 WARNINGS AND PRECAUTIONS). 

• XELJANZ/XELJANZ XR is contraindicated in patients with severe hepatic impairment; XELJANZ XR should not be used in patients with moderate hepatic impairment.

4.2 Recommended Dose and Dosage Adjustment

Rheumatoid Arthritis

XELJANZ/XELJANZ XR is to be used in combination with methotrexate.

XELJANZ/XELJANZ XR, monotherapy may be considered in cases of intolerance to methotrexate and to one or more DMARDs.

The recommended dose of XELJANZ is 5 mg administered twice daily (BID). The recommended dose of XELJANZ XR is 11 mg once daily.

A dosage of XELJANZ 10 mg BID is not recommended for the treatment of rheumatoid arthritis (see 7 WARNINGS AND PRECAUTIONS).

Switching between XELJANZ Tablets and XELJANZ XR Tablets: Where appropriate, patients treated with XELJANZ 5 mg BID may be switched to XELJANZ XR 11 mg once daily the day following the last dose of XELJANZ 5 mg.

Where appropriate, patients treated with XELJANZ XR 11 mg once daily may be switched to XELJANZ 5 mg BID 24 hours following the last dose of XELJANZ XR 11 mg.

Patients treated with XELJANZ XR 11 mg once daily who require a dose reduction due to renal or hepatic impairment or drug interactions may be switched to XELJANZ 5 mg once daily, 24 hours following the last dose of XELJANZ XR 11 mg once daily (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).

Psoriatic Arthritis

The recommended dose of XELJANZ is 5 mg administered BID in combination with MTX or another csDMARD. 

A dosage of XELJANZ 10 mg BID is not recommended for the treatment of psoriatic arthritis (see 7 WARNINGS and PRECAUTIONS, Thrombosis).

Ankylosing Spondylitis

The recommended dose of XELJANZ is 5 mg administered BID.

A dosage of XELJANZ 10 mg BID is not recommended for the treatment of ankylosing spondylitis (see 7 WARNINGS and PRECAUTIONS, Thrombosis).

Ulcerative Colitis

The recommended dose is 10 mg given orally BID for induction for at least 8 weeks and 5 mg given BID for maintenance.

Depending on therapeutic response; 10 mg BID may also be used for maintenance in some patients. However, the lowest effective dose possible should be used for maintenance therapy to minimize adverse effects (see 7 WARNINGS AND PRECAUTIONS).

XELJANZ induction therapy should be discontinued in patients who show no evidence of adequate therapeutic benefit by Week 16.

In patients who have responded to treatment with XELJANZ, corticosteroids may be cautiously reduced and/or discontinued in accordance with standard of care.

Dose Interruption or Discontinuation due to Serious Infections and Cytopenias

• Avoid use of XELJANZ/XELJANZ XR if a patient develops a serious infection until the infection is controlled.
• Dose interruption is recommended for management of anemia, lymphopenia, and neutropenia as described in Table 1 (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS).

Dose Modification in Patients with Renal or Hepatic Impairment, or Due to Drug Interactions

• Use XELJANZ with caution in patients with moderate (CLcr ≥30 and <60 mL/min) or severe (CLcr ≥15 and <30 mL/min) renal insufficiency (including patients with ESRD but not limited to those undergoing hemodialysis). Modified dosing is indicated in Table 2.
  • For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended in patients after dialysis.
  • Patients with severe renal insufficiency should remain on a reduced dose even after hemodialysis.
• Use XELJANZ with caution in patients with moderate hepatic impairment. Modified dosing is indicated in Table 2.
• XELJANZ XR is not recommended in patients with moderate hepatic impairment or moderate to severe renal insufficiency; XELJANZ 5 mg once daily may be considered.
• Modified dosing of XELJANZ/XELJANZ XR is recommended with concomitant CYP inhibitors as indicated in Table 3.
• Coadministration of potent inducers of CYP3A4 with XELJANZ/XELJANZ XR is not recommended. Coadministration of potent inducers of CYP3A4 (e.g. rifampin) with XELJANZ/XELJANZ XR may result in loss of efficacy or reduced clinical response to XELJANZ/XELJANZ XR (see 9.4 Drug-Drug Interactions).

Special Populations

Geriatrics (>65 years): No dosage adjustment is required in patients aged 65 years and older (see 7.1.4 Geriatrics and 10 CLINICAL PHARMACOLOGY). 

Pediatrics (<18 years of age): Health Canada has not authorized an indication for pediatric use. No data are available regarding the safety and efficacy of XELJANZ/XELJANZ XR in children aged from neonates to less than 18 years of age. Therefore XELJANZ/XELJANZ XR should not be used in this patient population (see 1.1 Pediatrics, 7.1.3 Pediatrics and 10 CLINICAL PHARMACOLOGY).   

4.4 Administration

XELJANZ/XELJANZ XR is to be taken orally with or without food.

Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew. 

4.5 Missed Dose

For a missed dose, resume at the next scheduled dose.

There is no experience with overdose of XELJANZ/XELJANZ XR (tofacitinib). There is no specific antidote for overdose with XELJANZ/XELJANZ XR. Treatment should be symptomatic and supportive. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicates that more than 95% of the administered dose is expected to be eliminated within 24 hours.

XELJANZ

Tablet: 5 mg tofacitinib (as tofacitinib citrate) are white, round, film coated tablets with Pfizer on one side and JKI 5 on the other side. The tablets are available in HDPE bottles with desiccant and child-resistant caps containing 60 film-coated tablets, and in foil / foil blisters containing 56 film-coated tablets.

Tablet: 10 mg tofacitinib (as tofacitinib citrate) are blue, round, film coated tablets with Pfizer on one side and JKI 10 on the other side. The tablets are available in HDPE bottles with desiccant and child-resistant caps containing 60 film-coated tablets, and in foil / foil blisters containing 56 film-coated tablets.

XELJANZ XR

Tablets: 11 mg tofacitinib (as tofacitinib citrate) are pink, oval extended-release-coated tablets. The tablets are available in HDPE bottles with desiccant and child-resistant caps containing 14 or 30 extended-release film-coated tablets.

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.

Retinal venous thrombosis

Retinal venous thrombosis (RVT) has been reported in patients treated with tofacitinib (see 8.2 Clinical Trial Adverse Reactions, Thromboembolism, Table 10 and 14.1 Clinical Trials by Indication, Rheumatoid Arthritis, Study RA-VI). Patients should be advised to promptly seek medical care if they experience symptoms suggestive of RVT.

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).

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 INTERACTION).

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-CLINICALTOXICOLOGY).

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).

8.1 Adverse Reaction Overview

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

The most common serious adverse reactions (SAEs) in rheumatoid arthritis clinical trials were osteoarthritis and serious infections, including pneumonia, cellulitis, herpes zoster, and urinary tract infection.

The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in rheumatoid arthritis clinical trials (occurring in ≥2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, nasopharyngitis, and diarrhea. Additionally, bronchitis, urinary tract infection, herpes zoster, RA, back pain and hypertension were also reported in the 5 mg BID XELJANZ group in the long-term extension trial.

The most common adverse reactions in rheumatoid arthritis clinical trials that resulted in discontinuation of XELJANZ were infections. Pneumonia was the most common adverse reactions leading to discontinuation of therapy, followed by blood creatinine increased and herpes zoster.

Asian patients had higher rates of herpes zoster, opportunistic infections, elevated transaminases (ALT, AST) and decreased WBCs. Asian patients with RA also have an increased risk of ILD (see 7.1.5 Asian Patients). Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients.

Ulcerative Colitis

In the induction studies, the most common categories of serious adverse events were gastrointestinal disorders and infections. The most common serious adverse events (excluding events reported as UC) were abdominal pain, anal abscess, and drug hypersensitivity. The most common adverse events (≥5%) were headache and nasopharyngitis.

In the maintenance study, the most common categories of serious adverse events were gastrointestinal disorders, infections, injuries, and nervous system disorders. All serious adverse events were single reports (excluding events reported as UC). The most common adverse events (≥5%) (excluding events reported as UC) in patients treated with 5 mg BID were nasopharyngitis, arthralgia, headache, and upper respiratory tract infection. In patients treated with 10 mg BID, the most common adverse events were nasopharyngitis, arthralgia, blood creatine phosphokinase increased, upper respiratory tract infection, rash, hypercholesterolemia, and herpes zoster.

In induction studies, adverse events were reported in 515 subjects (54.9%) treated with 10 mg BID and 155 subjects (55.0%) treated with placebo. In the maintenance study, adverse events were reported in 143 subjects (72.2%) treated with 5 mg BID, 156 subjects (79.6%) treated with 10 mg BID, and 149 subjects (75.3%) treated with placebo.

In induction and maintenance studies, the most frequent reason for study discontinuation was worsening of UC. Excluding discontinuations due to worsening of UC, the proportion of patients who discontinued due to adverse reactions was less than 5% in any of the XELJANZ or placebo treatment groups in these studies.

Four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg BID.

Overall, the safety profile observed in UC patients treated with XELJANZ was consistent with the safety profile of XELJANZ across indications. Dose-dependent risks seen in patients treated with XELJANZ 10 mg BID in comparison with 5 mg BID include the following: herpes zoster infections, serious infections, and NMSC.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions.  The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Rheumatoid Arthritis

During controlled clinical trials, 8.0% (11.0 events/100 patient-years) of patients in the 5 mg BID in the XELJANZ group were hospitalized due to serious adverse reactions compared to 7.8% (9.1 events/100 patient-years) and 3.8% (13.0 events/100 patient-years) of patients in the adalimumab and placebo group, respectively.

During the first 3 months of Phase 3 studies, serious infections (those requiring parenteral antibiotics or hospitalization) were reported in 0.7% (2.8 events/100 patient-years) and 0.2% (0.6 events/100 patient-years) of patients treated with XELJANZ or placebo, respectively. From 0-12 months, serious infections were reported in 2.4% (3.2 events/100 patient-years) of XELJANZ treated patients (see 7 WARNINGS AND PRECAUTIONS). In a post-authorization safety study, the frequency of pulmonary embolism was increased in patients treated with 10 mg BID XELJANZ (1.65%) compared to the TNF inhibitor (0.21%) and 5 mg BID XELJANZ (0.62%).

Deaths occurred in 0.4% (0.6 events/100 patient-years) of patients in the 5 mg BID XELJANZ group, compared to 0.5% (0.6 events/100 patient-years) and 0.2% (0.5 events/100 patient-years) of patients in the adalimumab and placebo groups, respectively. In a post-authorization safety study, all cause mortality was increased in patients treated with 10 mg BID XELJANZ (2.7%) compared to the TNF inhibitor (1.2%) and 5 mg BID XELJANZ treatment arms (1.8%).

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3 months in double-blind placebo-controlled studies was 7.8% for patients taking 5 mg BID of XELJANZ and 3.7% for placebo-treated patients. In the long-term extension trial, the proportion of patients who discontinued treatment due to any adverse reaction was 24.8% (6.78 events/100 patient-years) for all patients, 27.9% (6.67 events/100 patient-years) for patients taking 5 mg BID of XELJANZ, and 23.8% (6.83 events/100 patient-years) for patients taking 10 mg BID of tofacitinib.

Following completion of the Phase 2/3, open-label, uncontrolled, long-term extension follow-up trial (up to 114 months) from the Phase 2 studies and Phase 3 clinical program, there were 4040 subjects with 16113 patient-years of exposure to tofacitinib. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. Tofacitinib 10 mg BID is not recommended in RA patients. Overall, the safety profile of XELJANZ 5 mg BID in the long-term extension study was comparable to what was seen in the controlled clinical trials.

Table 5 below lists the adverse events (regardless of causality) occurring in ≥1% of patients treated with XELJANZ during the double-blind, placebo-controlled portion of the phase 3 RA studies. 

Overall Infections

In the five controlled trials, during 0 to 3 months exposure, the overall frequency of infections was 20% in the 5 mg BID XELJANZ group, and 18% in the placebo group.

In the long-term extension trial, overall frequency of infections was 67.7% (39.63 events/100 patient-years) in all XELJANZ group; 65.5% of patients (33.22 events/100 patient-years) and 68.4% of patients (42.24 events/100 patient-years) in the 5 mg and 10 BID of tofacitinib, respectively.

Infections were also reported in a post-authorization safety study in RA patients who were 50 years or older with at least one additional cardiovascular risk factor.

The most commonly reported infections were upper respiratory tract infections, nasopharyngitis, bronchitis, herpes zoster, and urinary tract infections.

Serious Infections

In the five controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.6 events/100 patient-years) who received placebo and 8 patients (2.8 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months exposure, the overall frequencies of serious infections were 2.4% (3.2 events/100 patient-years) for the 5 mg BID XELJANZ group.

In the long-term extension trial, the most common serious infections reported with XELJANZ included pneumonia, cellulitis, appendicitis, diverticulitis, gastroenteritis, urinary tract infection, and herpes zoster (see 7 WARNINGS AND PRECAUTIONS).

Serious infections were more frequently reported in subjects taking XELJANZ compared to TNF inhibitors (TNFi), and in patients treated with XELJANZ 10 mg BID compared to those treated with XELJANZ 5 mg BID in a post-authorization safety study (Study RA-VI), as shown in Table 6.

Tuberculosis

Cases of tuberculosis have been reported with treatment with XELJANZ.

In the five controlled Phase 3 trials, during 0 to 3 months exposure, no cases of tuberculosis were reported in patients who received placebo or 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, tuberculosis was reported in 0 patients who received 5 mg BID of XELJANZ. 

In the long-term extension trial, adjudicated tuberculosis events were reported in 0.6% patients (0.15 events/100 patient-years) who received XELJANZ; 0.4% of patients (0.10 events/100 patient-years) and 0.6% of patients (0.17 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.   

Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) (see 7 WARNINGS AND PRECAUTIONS.

Opportunistic Infections (excluding tuberculosis)

In the five controlled Phase 3 trials, during 0 to 3 months exposure, opportunistic infections were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, opportunistic infections were reported in 3 (0.3%) patients (0.3 events/100 patient-years) who received 5 mg BID of XELJANZ.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

The similar frequency of opportunistic infections was observed in the long-term extension trial with XELJANZ treatment up to 114 months.

Malignancy (excluding non-melanoma skin cancer)

In the five Phase 3 controlled trials, during 0 to 3 months exposure, malignancies (excluding non-melanoma skin cancer) were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months of exposure, malignancies (excluding non-melanoma skin cancer) were reported in 5 (0.4%) patients (0.6 events/100 patient-years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of malignancies (excluding non-melanoma skin cancer) was 3.1% (0.83 events/100 patient-years) in all XELJANZ-treated patients; 3.4% of patients (0.8 events/100 patient-years) and 3% of patients (0.84 events/100 patient-years) in the 5 mg and 10 mg BID of XELJANZ, respectively.

The most common types of malignancy (excluding non-melanoma skin cancer), including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma and malignant melanoma (see 7 WARNINGS AND PRECAUTIONS).

In a post-authorization safety study (Study RA-VI), malignancies (excluding NMSC) were observed more frequently in patients taking XELJANZ compared with patients taking TNFi (Table 7). Frequency of lung cancer was higher in patients taking XELJANZ 10 mg BID compared with patients taking XELJANZ 5 mg BID. Thyroid cancer was observed in 5, 2, and 0 subjects taking XELJANZ 5 mg BID, taking XELJANZ 10 mg BID, and TNFi, respectively.

Non-Melanoma Skin Cancer

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.

In the five Phase 3 controlled trials, during the 0 to 3 months exposure, NMSC was reported in 1 (0.2%) patient (0.6 events/100 patient-years) who received placebo and 2 (0.2%) patients (0.7 events/100 patient-years) who received 5 mg BID of XELJANZ.

During 0 to 12 months exposure, NMSC was reported in 3 (0.3%) patients (0.3 events/100 patient-years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of NMSC was 2.6% (0.71 events/100 patient-years) in all XELJANZ-treated patients; 2.5% of patients (0.6 events/100 patient-years) and 2.6% of patients (0.75 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.

In a post-authorization safety study (Study RA-VI), NMSC, including cutaneous squamous cell carcinoma, was more frequently observed in patients taking XELJANZ compared with patients taking TNFi (Table 8).

Mortality

In a post-authorization safety study (Study RA-VI), all-cause mortality was observed more frequently for patients taking XELJANZ (n=65/2911; 2.2%) compared with patients taking TNFi (n=17/1451; 1.2%). Related study data is presented in Table 9.

Thromboembolism

Venous thromboembolism, including pulmonary embolism, were observed more frequently in a post-authorization safety study (Study RA-VI), as shown in Table 10. Pulmonary embolism was observed more frequently with XELJANZ 10 mg BID than XELJANZ 5 mg BID. Deep vein thrombosis, and arterial thromboembolism were also observed in the study.

Major Adverse Cardiovascular Events (MACE), Including Myocardial Infarction

In a post-authorization study (Study RA-VI) the risk of MACE, including non-fatal myocardial infarction, was higher in patients treated with XELJANZ, compared to patients treated with TNFi (Table 11).  In the XELJANZ 5 mg BID, XELJANZ 10 mg BID, All XELJANZ, and TNFi treatment arms, there were a total of 19, 19, 38, and 11 patients with MI events, respectively. Of these totals, the number of patients with fatal MI events was 0, 3, 3, and 3, respectively, whereas the number of patients with non-fatal MI events was 19, 16, 35, and 8, respectively.

Gastrointestinal Perforations

In a post-authorization study (Study RA-VI), gastrointestinal perforations were observed in subjects treated with XELJANZ 5 mg BID, XELJANZ 10 mg BID, and TNF inhibitors (Table 12).

Fractures

In a post-authorization study (Study RA-VI) the incidence rate (IR) (95% CI) for fractures was 2.79 (95%CI: 2.34-3.30) for XELJANZ 5 mg BID, and 2.87 (95% CI: 2.40-3.40) for XELJANZ 10 mg BID, compared to 2.27 (95% CI: 1.87-2.74) for TNF inhibitors.

Psoriatic Arthritis

A total of 783 patients were treated with any dose of XELJANZ in PsA clinical studies resulting in 1238 patient-years of exposure. Of these, 635 patients were exposed to XELJANZ for at least one year.

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions (≥2%) in patients treated with XELJANZ 5 mg BID during the first 3 months in placebo‑controlled clinical studies were bronchitis, diarrhea, dyspepsia, headache, nasopharyingitis, nausea.

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3‑months of the double-blind placebo‑controlled studies was 3.2% for XELJANZ‑treated patients and 2.5% for placebo-treated patients.

Overall, the safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in patients with RA treated with XELJANZ. Incidence rates and types of adverse drug reactions, overall infections, serious infections, opportunistic infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA Phase 3 clinical studies. The incidence rates of tuberculosis, malignancies (excluding NMSC), and NMSC in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA Phase 3 clinical studies. 

Ankylosing Spondylitis

In the safety population of the combined Phase 2 and the Phase 3 clinical trials, a total of 420 patients were treated with study-specified dose XELJANZ corresponding to 233 patient-years of experience. Of these, 108 patients received XELJANZ 5 mg twice daily for 12 months or longer. Concomitant treatment with stable doses of cDMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.

The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients. The incidence rates and types of adverse drug reactions, overall infections, and serious infections reported in the controlled Phase 3 AS clinical study were similar to those reported in RA Phase 3 clinical studies. During the 16-week placebo-controlled period in study AS-I, the frequency of increased transaminases was 4.3% with XELJANZ 5 mg and 1.07% with placebo.

Ulcerative Colitis

Table 13 below lists adverse drug reactions reported by ≥1% of patients treated with XELJANZ – UC Phase 2 and Phase 3 Induction Studies

Overall Infections

In the randomised 8-week Phase 2/3 induction studies, the proportions of patients with infections were 21.1% (198 patients) in the XELJANZ 10 mg BID group compared to 15.2% (43 patients) in the placebo group. In the randomised 52-week Phase 3 maintenance study, the proportion of patients with infections were 35.9% (71 patients) in the 5 mg BID and 39.8% (78 patients) in the 10 mg BID XELJANZ groups, compared to 24.2% (48 patients) in the placebo group.

In the maintenance study, results suggested that the risk of opportunistic infection was possibly dose related: XELJANZ 10 mg BID (2.0%), XELJANZ 5 mg BID (1.0%), and placebo (0.5%). All opportunistic infections were herpes zoster infections. Herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

In the entire treatment experience with XELJANZ, the most commonly reported infection was nasopharyngitis, occurring in 18.2% of patients (211 patients). 

Serious Infections

The incidence rates and types of serious infections in the UC clinical trials were generally similar to those reported in RA Phase 3 clinical trials with XELJANZ.

Patients treated with XELJANZ 10 mg BID had a higher rate of serious infections compared to those treated with 5 mg BID. 

Opportunistic infections (excluding tuberculosis)

In the maintenance study, herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

Also, opportunistic herpes zoster infections (including serious cases, such as, disseminated, meningoencephalitis, ophthalmologic) were reported in patients treated with XELJANZ 10 mg BID. 

Malignancies (excluding NMSC)

In the controlled clinical studies (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. 

8.3 Less Common Clinical Trial Adverse Reactions

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

Blood and Lymphatic System Disorders: leukopenia, lymphopenia, neutropenia

Cardiovascular: congestive heart failure, myocardial infarction

Gastrointestinal Disorders: abdominal pain, appendicitis, gastrointestinal perforation

General Disorders and Administration Site Conditions: influenza

Hepatobiliary Disorders: hepatic steatosis

Infections and Infestations:  atypical mycobacterial infection, arthritis bacterial, bacteraemia, cellulitis, cytomegalovirus infection, disseminated tuberculosis, diverticulitis, encephalitis, gastroenteritis viral, herpes simplex, herpes zoster, meningitis cryptococcal, mycobacterium avium complex infection, necrotising fasciitis, pneumonia bacterial, pneumonia pneumococcal, pneumocystis jiroveci pneumonia, pyelonephritis, sepsis, staphylococcal bacteraemia, tuberculosis, tuberculosis of central nervous system, urosepsis, viral infection.

Injury, Poisoning and Procedural Complications: muscle strain, fall

Investigations: blood cholesterol increased, blood creatinine increased, blood creatine phosphokinase increased, gamma glutamyltransferase increased, hepatic enzyme increased, liver function test abnormal, low density lipoprotein increased, transaminases increased, weight increased,

Metabolism and Nutrition Disorders: dehydration, dyslipidemia, hyperlipidemia

Musculoskeletal and Connective Tissue Disorders: joint swelling, ligament sprain, musculoskeletal pain, tendonitis,

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): lymphoma, non-melanoma skin cancers, solid tumours  

Nervous System Disorders: paraesthesia

Psychiatric Disorders: insomnia

Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnoea, sinus congestion,  

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

Vascular disorders: arterial thrombosis, deep vein thrombosis, pulmonary embolism. 

Ulcerative Colitis

Blood and Lymphatic System Disorders: neutropenia, lymphopenia, leukopenia

Gastrointestinal Disorders: gastritis

General Disorders and Administration Site Conditions: oedema peripheral

Hepatobiliary Disorders: hepatic steatosis

Infections and Infestations: pneumonia, pyelonephritis, cellulitis, herpes simplex, tuberculosis, arthritis bacterial, cytomegalovirus infection, diverticulitis

Injury, Poisoning and Procedural Complications: muscle strain

Investigations: hepatic enzyme increased, transaminases increased, blood creatinine increased, liver function test abnormal, low density lipoprotein increased

Metabolism and Nutrition Disorders: dehydration

Musculoskeletal and Connective Tissue Disorders: tendonitis, joint swelling

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): non-melanoma skin cancers, solid cancers, lymphomas  

Nervous System Disorders: paraesthesia

Respiratory, Thoracic and Mediastinal Disorders: sinus congestion

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Laboratory Tests – Rheumatoid Arthritis and Ulcerative Colitis

Creatine Kinase

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.

CK levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis (see 7 WARNINGS AND PRECAUTIONS)

ECG Findings

In placebo-controlled Phase 2 clinical trials, steady-state treatment with 5-10 mg BID XELJANZ was associated with statistically significant 4-7 bpm decreases in heart rate and 4-10 ms increases in the PR interval compared with placebo (see 7WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).

Lipids

Treatment with XELJANZ was associated with dose related increases in lipid parameters.

Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) generally reached maximal effects at 6 weeks following initiation of XELJANZ in the controlled RA double-blind clinical trials. Changes in lipid parameters from baseline through the end of the study (6-12 months) in the controlled clinical studies in RA are summarized below:

• Mean LDL cholesterol increased by 14% in the XELJANZ 5 mg BID arm.
• Mean HDL cholesterol increased by 16% in the XELJANZ 5 mg BID arm.
• Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In the five controlled RA clinical trials, 4.4% of patients treated with 5 mg BID, initiated lipid-lowering medication while on study.  

In the RA long-term safety population, elevations in the lipid parameters remained consistent with what was seen in the controlled clinical studies.

Increases of total cholesterol, LDL cholesterol, and HDL cholesterol were also reported in a post-authorization safety (Study RA-VI; Table 15). 

Liver Enzyme Tests

Confirmed increases in liver enzymes >3x upper limit of normal (ULN) were uncommonly observed. In those patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.

In the controlled portion of the RA Phase 3 monotherapy study (0-3 months), ALT elevations >3x ULN were observed in 1.65% and 0.41% of patients receiving placebo and 5 mg BID, respectively. In this study, AST elevations >3x ULN were observed in 1.65%, and 0.41% of patients receiving placebo and 5 mg BID, respectively.

In the controlled portion of the RA Phase 3 studies on background DMARDs (0-3 months), ALT elevations >3x ULN were observed in 0.9% and 1.24% of patients receiving placebo and 5 mg BID, respectively. In these studies, AST elevations >3x ULN were observed in 0.72% and 0.52% of patients receiving placebo and 5 mg BID, respectively.

In the RA long-term extension trial, ALT and AST elevations greater than 3x ULN were observed in 2.2% and 1.1% of all XELJANZ-treated patients, respectively. Overall, total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5x and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively) in all patients treated with XELJANZ.

In RA patients taking 5 mg BID of XELJANZ, the ALT and AST elevations greater than 3x ULN were observed in 2.4% and 1.3% of patients, respectively. There was no subject who had the total bilirubin elevations greater than 2x ULN. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.4% and 0.1% of patients, respectively) and AST (0.2% and 0% of patients, respectively).

In RA patients taking 10 mg BID of tofacitinib, the ALT and AST elevations greater than 3x ULN were observed in 2.1% and 1.1% of patients, respectively. The total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively).

Two patients treated with 10 mg BID of tofacitinib in the RA long-term extension trial were assessed as probable DILI by the adjudication committee. One of the two patients had other possible causes of alcohol intake and methotrexate.

Elevations of ALT and AST were reported more frequently in patients taking XELJANZ compared with patients taking TNFi in a post-authorization safety study (Study RA-VI; Table 16).

In the clinical studies in UC, changes in liver enzyme tests observed with XELJANZ 5 mg BID treatment were similar to the changes observed in clinical studies in RA.

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 dose.

One patient 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. 

Lymphocytes

In the five controlled RA clinical trials, confirmed decreases in absolute lymphocyte counts below 0.5 x10⁹ cells/L occurred in 0.2% of patients for the 5 mg BID XELJANZ group during 12 months of exposure.

Confirmed lymphocyte counts less than 0.5 x10⁹ cells/L were associated with an increased incidence of treated and serious infections (see 7 WARNINGS AND PRECAUTIONS).

In the RA long-term extension trial, cases of lymphopenia have been reported in 181 (4.0%) patients (1.11 events/100 patient-years) treated with XELJANZ; 4.5% of patients (1.07 events/100 patient-years) and 3.9% of patients (1.12 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in absolute lymphocyte counts below 0.5 x10⁹ cells/L occurred in 1.3% of all XELJANZ-treated patients; 1.1% of patients for the 5 mg BID XELJANZ group, and 1.4% of patients for the 10 mg BID tofacitinib group.

In a post-authorization safety study (Study RA-VI) the median decrease in lymphocyte counts were greater in patients taking XELJANZ (-0.21) compared with patients taking TNFi (0.37).

In the 52-week maintenance study in UC, a single absolute lymphocyte count below 0.5 x10⁹ cells/L was reported in 2.6% (n=5) of patients treated with 10 mg BID, and was not reported in patients treated with 5 mg BID or placebo. No patients in any treatment group had confirmation of a lymphocyte count below 0.5 x10⁹ cells/L based on two sequential tests.

Neutrophils

In the controlled RA clinical studies, confirmed decreases in ANC below 1x10⁹ cells/L occurred in 0.08% of patients in the 5 mg BID XELJANZ group during 12 months of exposure. There were no confirmed decreases in ANC below 0.5 x10⁹ cells/L observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term extension trial, cases of neutropenia have been reported in 86 (1.9%) patients (0.52 events/100 patient-years) treated with XELJANZ; 4.0% of patients (0.97 events/100 patient-years) and 1.2% of patients (0.35 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in ANC below 1x10⁹ cells/L occurred in 0.2% in all XELJANZ-treated patients; 0.4% of patients for the 5 mg BID XELJANZ group, and 0.1% of patients for the 10 mg BID tofacitinib group. 

In the clinical studies in UC, changes in neutrophils observed with XELJANZ treatment were similar to the changes observed in clinical studies in RA.

Serum Creatinine

In the controlled RA clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12‑month pooled safety analysis; however, with increasing duration of exposure in the long-term extension trial, up to 6.9% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

In the UC studies, an increase of more than 50% in serum creatinine was reported in 1.6% of patients predominantly treated with XELJANZ 5 mg BID, and 3.4% of those predominantly treated with XELJANZ 10 mg BID.  

Laboratory Tests – Psoriatic Arthritis

In the controlled clinical trials in PsA, changes in hematologic and clinical chemistry findings observed with XELJANZ treatment were similar to the changes observed in Phase 3 clinical trials in RA. 

Laboratory Tests - Ankylosing Spondylitis

In the controlled clinical trials in AS, changes in hematologic and clinical chemistry findings observed with XELJANZ treatment were similar to the changes observed in Phase 3 clinical trials in RA.

8.5 Post-Market Adverse Reactions

Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: drug hypersensitivity reactions including angioedema and urticaria (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS)

Serious infections: viral reactivation (hepatitis B reactivation) (see 7 WARNINGS AND PRECAUTIONS)

9.2 Drug Interactions Overview

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 80 times the steady state C_max of a 5 and 10 mg BID dose in patients treated with tofacitinib. In vitro studies also indicated a low risk of induction of CYP3A4 (2-fold mRNA at 6.25 µM), CYP2B6 (2-fold mRNA at 12.5 µM), and CYP1A2 (no enzyme changes) at clinically relevant concentrations (total C_max of 0.186 µM).

In vitro, tofacitinib is a substrate for multidrug resistance (MDR) 1, but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1/1B3, or organic cationic transporter (OCT) 1/2. In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, MDR1, organic anion transporter (OAT) P1B1/1B3, OCT2, OAT1/3, cationic transporters or multidrug resistance‑associated protein (MRP) at therapeutic concentrations is also low.

Tofacitinib exposure is increased when XELJANZ is coadministered with potent CYP3A4 inhibitors (e.g., ketoconazole) or when administration of one or more concomitant medications results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin). Inhibitors of CYP2C19 or P-glycoprotein are unlikely to alter the PK of tofacitinib.

The in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state C_max of a 5 and 10 mg BID dose in RA, PsA and UC patients.  

The oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates.

9.4 Drug-Drug Interactions

The impact of extrinsic factors on tofacitinib pharmacokinetics is summarized in Figure 1 and 2 with dosage adjustment recommendations.

Figure 1: Impact of Co-administered of drugs on Pharmacokinetics Tofacitinib

Note: Reference group is administration of tofacitinib alone; PK=Pharmacokinetics; CI=Confidence Interval

^a In RA patients the recommended dose is XELJANZ 5 mg once daily. In UC patients receiving 10 mg BID, XELJANZ dosage should be reduced to 5 mg BID, and in UC patients receiving 5 mg BID, XELJANZ dosage should be reduced to 5 mg once daily.

Figure 2: Impact of Tofacitinib on Pharmacokinetics of Co-administered Drugs

Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion; PK=Pharmacokinetics; CI=Confidence Interval

Drugs that Decrease Heart Rate and/or Prolong the PR Interval

XELJANZ resulted in a decrease in heart rate and an increase in the PR interval (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS). Caution should be observed if XELJANZ/XELJANZ XR is used concomitantly with other drugs that lower heart rate and/or prolong the PR interval, such as antiarrhythmics, beta blockers, alpha2 adrenoceptor agonists, non-dihydropyridine calcium channel blockers, digitalis glycosides, cholinesterase inhibitors, sphingosine-1 phosphate receptor modulators, and some HIV protease inhibitors.

Combination with other therapies

XELJANZ/XELJANZ XR has not been studied and is not indicated to be used in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, IL‑17 antagonists, IL-12/IL-23 antagonists, anti‑CD20 monoclonal antibodies, anti-integrins, selective co-stimulation modulators, and potent immunosuppressants such as azathioprine, 6‑mercaptopurine, cyclosporine, and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.

The use of XELJANZ/XELJANZ XR in combination with phosphodiesterase 4 inhibitors has not been studied in XELJANZ clinical trials.

9.5 Drug-Food Interactions

Grapefruit juice affects CYP450 3A-mediated metabolism and concomitant administration with XELJANZ/XELJANZ XR should be avoided.

9.6 Drug-Herb Interactions

St John’s Wort is a CYP3A4 inducer and co-administration with XELJANZ/XELJANZ XR may result in loss of or reduced clinical response.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10.1 Mechanism of Action

Tofacitinib is a potent, selective inhibitor of the JAK family of kinases with a high degree of selectivity against other kinases in the human genome. In kinase assays, tofacitinib, inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In cellular settings where JAK kinases signal in pairs, tofacitinib preferentially inhibits signaling by heterodimeric receptors associated with JAK3 and/or JAK1 with functional selectivity over receptors that signal via pairs of JAK2.  Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common gamma chain-containing receptors for several cytokines, including IL-2, -4,-7,-9, -15, and -21. These cytokines are integral to lymphocyte activation, proliferation, and function and inhibition of their signaling may thus result in modulation of multiple aspects of the immune response. In addition, inhibition of JAK1 will result in attenuation of signaling by additional pro-inflammatory cytokines, such as IL-6 and Type I interferons. At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of JAK2 signaling.

10.2 Pharmacodynamics

In patients with RA, treatment with XELJANZ (tofacitinib) was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets were small and inconsistent. The clinical significance of these changes is unknown. 

Changes in total serum IgG, M, and A levels over 6-month dosing of patients with RA were small, not dose-dependent and similar to those seen on placebo.

After treatment with XELJANZ in patients with RA, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the half-life.

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.

Similar changes in T cells, B cells and serum CRP have been observed in patients with active PsA, although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active PsA.

Patients with UC were not studied.

10.3 Pharmacokinetics (PK)

XELJANZ

Following oral administration of XELJANZ, the PK profile of XELJANZ is characterized by rapid absorption (peak plasma concentrations are reached within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases in systemic exposure in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after BID administration.

A geometric mean accumulation ratio (Rac) of 1.12 following BID dosing indicates little difference between single dose and steady state concentrations as well as the predictability of steady state PK from single dose data. The dose-AUC relationship was adequately described by a linear model fit to log-both sides transformed data while the dose-C_max relationship were best described by a nonlinear sigmoidal, hyperbolic model fit to log-transformed C_max data. Although the nonlinear model provided better description of the dose-C_max relationship relative to a linear model, when compared to 5 mg, the mean model predicted relative changes in dose-normalized C_max were approximately +7% for 10 mg, +2% for 30 mg, and -10% for 50 mg doses. These small changes from linearity support the conclusion that XELJANZ C_max is approximately dose proportional at least up to 5 times the 10 mg dose. 

XELJANZ XR

Following oral administration of XELJANZ XR, peak plasma tofacitinib concentrations are reached at 4 hours and the half‑life is ~6 hours. Steady state concentrations are achieved within 48 hours with negligible accumulation (accumulation ratio: 1.12) after once daily (QD) administration. At steady state, C_min for XELJANZ XR 11 mg QD is approximately 29% lower and C_trough is approximately 26% lower compared to XELJANZ 5 mg BID. Area under the curve (AUC) and C_max of tofacitinib for XELJANZ XR 11 mg administered once daily are equivalent to those of XELJANZ 5 mg administered BID. 

Pharmacokinetics in Patients with Moderately to Severely Active UC

Population PK analysis in UC patients indicated that PK characteristics were similar to that of RA patients. There were no clinically relevant differences in tofacitinib exposure (AUC), based on age, weight, gender and race, after accounting for differences in renal function (i.e., creatinine clearance) between patients. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 23% to 25% in UC patients. 

Absorption:

XELJANZ

Tofacitinib is well-absorbed, with an absolute oral bioavailability of 74% following administration of XELJANZ. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while C_max was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meal. 

XELJANZ XR

Coadministration of XELJANZ XR with a high-fat meal resulted in no changes in AUC while C_max was increased by 27% and T_max was extended by approximately 1 hour. 

Distribution:

After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is ~40%). Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. 

Metabolism:

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule. 

Elimination:

Approximately 94% of a radioactive dose of XELJANZ was recovered from the urine (80%) and feces (14%), with the majority of excreted radioactivity recovered within 24 hours after dosing. 

C_max = maximum plasma concentration; t_½ = terminal elimination half-life; AUC_0-24 = area under the plasma concentration-time curve from time 0 to 24 hours post dose. 

Special Populations and Conditions

Rheumatoid Arthritis and Ulcerative Colitis

Pediatrics (<18 years of age): The pharmacokinetics, safety and effectiveness of tofacitinib in pediatric patients have not been established; therefore, XELJANZ/XELJANZ XR should not be used in this patient population. Pharmacokinetic of tofacitinib was characterized in an open-label, non-randomized, multi-center, Phase 1 study conducted in pediatric patients (aged from 2 to less than 18 years) with juvenile idiopathic arthritis. A total of 26 patients were enrolled in this study and treated at dosing regimens based on the children’s age and body weight. The study consisted of 3 cohorts based on subject age with at least 8 subjects per cohort. Based on limited data, the PK profile of tofacitinib appears to be characterized by a rapid absorption (peak plasma concentrations were reached within 0.5-1 hour) and a rapid elimination. The average half-lives for tofacitinib were approximately 2.6h, 1.9h, and 1.8h for the Cohorts 1 (12 to <18 years), 2 (6 to <12 years) and 3 (2 to <6 years), respectively, with individual values ranging from 1.4 to 3.1h across all cohorts.

Geriatrics (>65 years of age): Population PK analysis in RA patients indicated that geriatric patients 80 years of age were estimated to have <5% higher XELJANZ AUC relative to the mean age of 55 years. Of the 3315 patients who enrolled in studies I to V, a total of 505 (15%) RA patients were 65 years of age and older, including 71 (2%) patients 75 years and older. The frequency of serious infection and other events among XELJANZ treated subjects 65 years of age and older was higher than those under the age of 65.

Of the 4362 patients enrolled in Study RA-VI, 1353 patients were 65 years of age and older (891 patients were treated with XELJANZ and 462 patients were treated with TNFi), including 183 patients over 70 years of age (115 patients treated with XELJANZ and 68 patients treated with TNFi). 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) in patients 65 years of age and older was higher than among those under the age of 65.

There were not enough geriatric patients treated with XELJANZ (n=77) in the UC program to adequately study the effects of XELJANZ in this population. As there is a higher incidence of infections in the geriatric population in general, caution should be used when treating the geriatric (see 7 WARNINGS AND PRECAUTIONS).

Sex: Based on population PK analysis, female RA patients were estimated to have 7% lower XELJANZ AUC compared to male RA patients. Female UC patients were estimated to have 15.2% higher XELJANZ AUC compared to male UC patients.

Race: In RA patients, no major differences (<5%) were estimated in XELJANZ AUC between White, Black and Asian RA patients by population PK analysis. In UC patients, population PK analysis indicated that Asian patients had 7.3% higher XELJANZ AUC compared to non-Asian patients. There was a higher incidence of adverse events in Asian patients. Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients (see 7 WARNINGS AND PRECAUTIONS).

Body Weight: Population PK analysis in RA patients indicated that systemic exposure (AUC) of XELJANZ in the extremes of body weight (40 kg, 140 kg) were similar to that of a 70 kg patient. An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (C_max) and lower trough (C_min) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (% coefficient of variation) in AUC of XELJANZ is estimated to be approximately 27%. Population PK analysis in UC patients also indicated that XELJANZ AUC did not significantly change with patient body weight.

Hepatic Impairment: XELJANZ/XELJANZ XR is contraindicated in patients with severe hepatic impairment (see 2 CONTRAINDICATIONS). Subjects with mild and moderate hepatic impairment had 3%, and 65% higher XELJANZ AUC, respectively, compared with healthy subjects.

No dose adjustment of XELJANZ/XELJANZ XR is required in patients with mild hepatic impairment. XELJANZ XR has not been studied in patients with moderate and severe hepatic impairment. Therefore, XELJANZ XR should not be used in patients with moderate hepatic impairment.

The recommended total daily dose in patients with moderate hepatic impairment is half the total daily dose recommended for patients with normal hepatic function. The recommended dose is XELJANZ 5 mg BID when the indicated dose in the presence of normal hepatic function is XELJANZ 10 mg BID; the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal hepatic function is XELJANZ 5 mg BID (see 4 DOSAGE AND ADMINISTRATION).

XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology and should not be used in these populations.

Renal Impairment: Subjects with mild, moderate, and severe renal impairment had 37%, 43% and 123% higher XELJANZ AUC, respectively, compared with healthy subjects.In subjects with ESRD undergoing hemodialysis, the contribution of dialysis to the total clearance of tofacitinib was relatively small.

In subjects with ESRD undergoing hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib. Dose adjustment is recommended in ESRD patients undergoing hemodialysis (see 4 DOSAGE AND ADMINISTRATION).

No dose adjustment of XELJANZ/XELJANZ XR is required in patients with mild renal impairment. XELJANZ XR has not been studied in patients with moderate and severe renal impairment. Therefore, XELJANZ XR is not recommended in patients with moderate and severe renal impairment, including patients with ESRD undergoing hemodialysis.

The recommended total daily dose in patients with moderate or severe renal impairment, including patients with ESRD but not limited to those undergoing hemodialysis, is half the total daily dose recommended for patients with normal renal function. The recommended dose is XELJANZ 5 mg BID when the indicated dose in the presence of normal renal function is XELJANZ 10 mg BID; the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal renal function is XELJANZ 5 mg BID (see 4 DOSAGE AND ADMINISTRATION).

In clinical trials, XELJANZ/XELJANZ XR was not evaluated in patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.

Genetic Polymorphism: Mean C_max and AUC_0-¥ values of tofacitinib following administration of XELJANZ in poor metabolizers of CYP2C19 (carriers of CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3 alleles) were approximately 15% and 17% greater, respectively, than those in normal metabolizers, indicating that CYP2C19 is a minor contributor of XELJANZ clearance.

The impact of intrinsic factors on tofacitinib following administration of XELJANZ pharmacokinetics is summarized in Figure 3 with dosage adjustment recommendations. 

Figure 3: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics 

PK=Pharmacokinetics; CI=Confidence Interval

Note: Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.

^a In RA patients the recommended dose is XELJANZ 5 mg once daily. In UC patients the recommended dose is half the total daily dose indicated for patients with normal renal and hepatic function, i.e., the recommended dose is XELJANZ 5 mg BID when the indicated dose in the presence of normal renal and hepatic function is XELJANZ 10 mg BID, and the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal renal and hepatic function is XELJANZ 5 mg BID.

^b Supplemental doses are not necessary in patients after dialysis. 

Psoriatic Arthritis

Results from population PK analysis in patients with active PsA were consistent with those in patients with RA.

Ankylosing Spondylitis

Results from population PK analysis in patients with active AS were consistent with those in patients with RA.

Store between 15°C and 30°C.

This information is not available for this drug product.

Control #: 272662
AUG 11, 2023