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XELJANZ (tofacitinib)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

 Oral

Tofacitinib tablets / 5 mg tofacitinib (as tofacitinib citrate)
 

Tofacitinib extended-release tablets / 11 mg tofacitinib (as tofacitinib citrate)

 

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

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.

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

Limitations of use: Use of XELJANZ/XELJANZ XR in combination with biological disease-modifying anti-rheumatic drugs(bDMARDs) or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Pediatrics (<18 years of age)

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

Geriatrics (>65 years of age)

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

Contraindications

XELJANZ/XELJANZ XR (tofacitinib) should not be administered to patients with known hypersensitivity to tofacitinib or any of its components. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

Warnings And Precautions

WARNING: RISK OF SERIOUS INFECTIONS

Patients treated with XELJANZ/XELJANZ XR (tofacitinib) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled.

Reported infections include:

  • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use.
  • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized disease.
  • Bacterial, viral, and other infections due to opportunistic pathogens.

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

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

MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications (see WARNINGS and PRECAUTIONS).

General

Specific to XELJANZ XR
As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.

Cardiovascular

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

Gastrointestinal Perforations

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

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

Hepatic

Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg BID for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3 x ULN and bilirubin elevations greater than 2 x ULN, which required hospitalization and a liver biopsy.

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

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

Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving immunomodulatory agents, including biologic DMARDs and XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infections, and listeriosis were reported with XELJANZ. 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).

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

  • with chronic or recurrent infections,
  • who have been exposed to tuberculosis,
  • with a history of a serious or an opportunistic infection,
  • who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or
  • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. Caution is also recommended in patients with a history of chronic lung disease as they may be more prone to infections. Events of interstitial lung disease (some of which had a fatal outcome) have been reported in patients treated with XELJANZ in clinical trials and in the post-marketing setting.

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection.
For discontinuation and monitoring criteria for lymphopenia see Monitoring and Laboratory Tests.

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

Tuberculosis

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

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

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

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

Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ.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.

Interstitial lung disease

Events of interstitial lung disease (ILD) have been reported in clinical trials with XELJANZ in rheumatoid arthritis patients, 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 Special Populations).

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

Immune

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 in rheumatoid arthritis patients and is not recommended (see DRUG INTERACTIONS section).

Immunizations

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

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

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

In a randomized, double-blind, placebo-controlled study in 200 adult rheumatoid arthritis 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.

Malignancies and Lymphoproliferative Disorder

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

Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy. Recommendations for non-melanoma skin cancer are presented below.

In the 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 studies in patients treated with XELJANZ. Patients with rheumatoid arthritis, 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.

Non melanoma Skin Cancer
Nonmelanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ.
Periodic skin examination is recommended.

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 ESRD undergoing dialysis.

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

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 inthe XELJANZ rheumatoid arthritis clinical trials. CK levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis.

Special Populations

Pregnant Women

XELJANZ/XELJANZ XR should not be used during pregnancy. There are no adequate and well-controlled studies on the use of XELJANZ/XELJANZ XR in pregnant women. XELJANZ has been shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility, parturition, and peri/postnatal development (see TOXICOLOGY section).

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

Nursing Women

XELJANZ was secreted in milk of lactating rats.  It is not known whether XELJANZ/XELJANZ XR is excreted in human milk. Women should not breastfeed while being treated with XELJANZ/XELJANZ XR (see TOXICOLOGY section).

Pediatrics (<18 years of age)

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

Geriatrics (>65 years of age)

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

Asian patients

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

Laboratory Parameters

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

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

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

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

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

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

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

Liver Enzyme Elevations
Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver enzymes and prompt investigation of the cause of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, XELJANZ/XELJANZ XR administration should be interrupted until this diagnosis has been excluded.

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.

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. Patients should be managed according to local clinical guidelines for the management of hyperlipidemia.

Monitoring and Laboratory Tests

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

Liver enzyme tests are recommended. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded.

Assessment of renal function is recommended prior to initiation of XELJANZ/XELJANZ XR.

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

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

Adverse Reactions

Adverse Drug Reaction Overview

During controlled clinical trials, 8.0% (11.0 events/100 patient years) of patients in the 5 mg twice daily in the XELJANZ groupwere 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. Deaths occurred in 0.4% (0.6 events/100 patient years) of patients in the 5 mg twice daily 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.

The most common serious adverse reactions were serious infections, including pneumonia, cellulitis, herpes zoster, and urinary tract infection. During the first 3 months, 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 WARNINGS AND PRECAUTIONS).

The most commonly reported adverse reactions during the first 3 months in controlled clinicaltrials (occurring in ≥ 2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were upper respiratory tract infections (4.4% in the 5 mg twice daily group), headache (4.4% in the 5 mg twice daily group), nasopharyngitis (3.9% in the 5 mg twice daily group), and diarrhea (3.7% in the 5 mg twice daily group).

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 twice daily of XELJANZ and 3.7% for placebo-treated patients. The most common adverse reactions that resulted in discontinuation of XELJANZ were infections. The most common infections resulting in discontinuation of therapy were herpes zoster and pneumonia.

Asian patients

Asian patients had higher rates of herpes zoster, opportunistic infections, interstitial lung disease, elevated transaminases (ALT, AST) and decreased WBCs. Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1 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 rheumatoid arthritis studies.

Table 1: Summary of AdverseEvents reported by ≥ 1 % of patients treated with XELJANZ (All Causalities) - All Phase 3 Studies (up to 3 months)

Body

System/Adverse

Event

XELJANZ

5mg   BID

(N=1216)

Placebo

(N=681)

Adalimumab

40 mg  SC  q2w

(N=204)

Infections and infestations
Upper respiratory tract infection53 (4.4)23 (3.4)7 (3.4)
Nasopharyngitis48 (3.9)19 (2.8)7 (3.4)
Urinary tract infection25 (2.1)12 (1.8)7 (3.4)
Bronchitis14 (1.2)10 (1.5)4 (2.0)
Blood and lymphatic system disorders
Anemia15 (1.2)8 (1.2)0
Metabolism and nutrition disorders
Hypercholesterolaemia12 (1.0)3 (0.4)1 (0.5)
Nervous system disorders
Headache54 (4.4)15 (2.2)5 (2.5)
Dizziness13 (1.1)8 (1.2)3 (1.5)
Vascular disorders
Hypertension20 (1.6)7 (1.0)0
Gastrointestinal disorders
Diarrhoea45 (3.7)16 (2.3)2 (1.0)
Nausea32 (2.6)18 (2.6)3 (1.5)
Dyspepsia19 (1.6)11 (1.6)3 (1.5)
Abdominal pain upper23 (1.9)5 (0.7)3 (1.5)
Vomiting21 (1.7)10 (1.5)0
Constipation16 (1.3)6 (0.9)2 (1.0)
Gastritis12 (1.0)7 (1.0)0
Gastroenteritis12 (1.0)5 (0.7)0
Hepatobiliary Disorders
Alanine aminotransferase increased14 (1.2)7 (1.0)1 (0.5)
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis17 (1.4)17 (2.5)1 (0.5)
Back pain18 (1.5)5 (0.7)1 (0.5)
Arthralgia13 (1.1)16 (2.3)4 (2.0)
General disorders and administration site conditions
Oedema peripheral17 (1.4)16 (2.3)3 (1.5)
Pyrexia13 (1.1)5 (0.7)1 (0.5)

Overall Infections

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

The most commonly reported infections were upper respiratory tract infections and nasopharyngitis, 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 twice daily of XELJANZ.

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

The most common serious infections reported with XELJANZ included pneumonia, urinary tract infection, and herpes zoster (see WARNINGS AND PRECAUTIONS).

Tuberculosis

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

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

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 WARNINGS AND PRECAUTIONS).

Opportunistic Infections (excluding tuberculosis)

In the five controlled 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 twice daily of XELJANZ.

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

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

Malignancy (excluding nonmelanoma skin cancer)

In the five controlled trials, during the 0 to 3 months exposure, malignancies (excluding nonmelanoma 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 twice daily of XELJANZ.

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

The most common types of malignancy, (excluding nonmelanoma 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 WARNINGS AND PRECAUTIONS).

Nonmelanoma skin cancer

In the five controlled trials, during the 0 to 3 months exposure, nonmelanoma skin cancer 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 twice daily of XELJANZ.

During the 0 to 12 months exposure, nonmelanoma skin cancer was reported in 3 (0.3%) patients (0.3 events/100 patient years) who received 5 mg twice daily of XELJANZ.

Less Common Clinical Trial Adverse Drug Reactions(<1%)

Blood and lymphatic system disorders: Neutropenia

Cardiovascular: congestive heart failure, myocardial infarction

Gastrointestinal disorders: abdominal pain

General disorders and administration site conditions: Influenza

Hepatobiliary Disorders: Hepatic steatosis

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

Injury, Poisoning and Procedural Complications: Muscle strain, Fall

Investigations: Transaminases increased, blood creatinine increased, gamma glutamyltransferase increased, liver function test abnormal, Weight increased, Blood creatine phosphokinase increased

Metabolism and nutrition disorders: Dehydration

Musculoskeletal and connective tissue disorders: Tendonitis, joint swelling

Neoplasm benign, malignant and unspecified (Including Cysts and Polyps): Nonmelanoma skin cancers

Nervous system disorders: Paraesthesia

Respiratory, thoracic and mediastinal disorders: Sinus congestion, cough

Skin and subcutaneous tissue disorders: Erythema, pruritus

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Tests

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 in the XELJANZ rheumatoid arthritis clinical trials. CK levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis (see WARNINGS and PRECAUTIONS).

ECG Findings:In placebo-controlled phase 2 clinical trials in patients with rheumatoid arthritis, 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 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests,DRUG INTERACTIONS).

Lipids
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 double-blind clinical trials. Changes in lipid parameters from baseline through the end of the study (6-12 months) in the controlled clinical studies 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 clinical trials, 4.4% of patients treated with 5 mg BID, initiated lipid-lowering medication while on study.

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

Liver Enzyme Tests
Confirmed increases in liver enzymes >3x upper limit of normal (ULN) were uncommonly observed. In 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 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 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 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.

Lymphocytes
In the five controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.2% of patients for the 5 mg BID XELJANZ group during 12 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections (see WARNINGS and PRECAUTIONS).

Neutrophils
In the controlled clinical studies, confirmed decreases in ANC below 1000/mm3 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 500/mm3 observed in any treatment group.

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

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical studies (see WARNINGS AND PRECAUTIONS).

Serum creatinine
In the controlled 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 extensions, up to 2% 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.

Drug Interactions

Overview

The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19.

In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 185 times the steady state Cmax of a 5 mg BID dose.

In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters 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 rheumatoid patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in RA patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in RA patients.

Drug-Drug Interactions

Table 2: Summary of Drug-Drug Interactions

Drug

Reference

Effect

Clinical comment

Methotrexate

CT

Coadministration with methotrexate (15-25 mg MTX once weekly) had no effect on the PK of tofacitinib and decreased methotrexate AUC and Cmax by 10% and 13% respectively.

No dose adjustment is required for either drug.

Ketoconazole

CT

Coadministration of ketoconazole, a strong CYP3A4 inhibitor, with a single dose of XELJANZ increased the AUC and Cmax of tofacitinib by 103% and 16%, respectively

XELJANZ XR is not recommended in patients coadministered with strong inhibitors of CYP3A4.
 

Maximum recommended dose is XELJANZ 5 mg once daily when coadministered with strong inhibitors of CYP3A4

Fluconazole

CT

Coadministration of fluconazole, a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C19, increased the AUC and Cmax of tofacitinib by 79% and 27%, respectively

XELJANZ XR is not recommended in patients coadministered with medications that result in moderate inhibition of CYP3A4 and potent inhibition of CYP2C19.
 

Maximum recommended dose is XELJANZ 5 mg once daily  when coadministered with one or more medications that result in moderate inhibition of CYP3A4 and potent inhibition of CYP2C19

Tacrolimus and Cyclosporine

CT

Coadministration of tacrolimus, a mild inhibitor of CYP3A4, increased the AUC of tofacitinib by 21% and decreased the Cmax of tofacitinib by 9%.
 

Coadministration of cyclosporine, a moderate inhibitor of CYP3A4, increased the AUC of  tofacitinib by 73% and decreased Cmax of tofacitinib by 17%.

There is a risk of added immunosuppression when XELJANZ/XELJANZ XR is co-administered with potent immunosuppressive drugs (e.g: tacrolimus, cyclosporine, azathioprine). The combined use with these potent immunosuppressives has not been studied in rheumatoid arthritis patients and is not recommended.

Rifampin

CT

Coadministration of rifampin, a strong CYP3A4 inducer, decreased the AUC and Cmax of tofacitinib by 84% and 74%, respectively

Coadministration of XELJANZ/XELJANZ XR with potent inducers of CYP3A4 may result in loss of or reduced clinical response /efficacy.

Midazolam

CT

Coadministration of XELJANZ with midazolam, a highly sensitive CYP3A4 substrate, had no effect on midazolam PK

No dosage adjustment is required for CYP3A4 substrates such as midazolam.

Oral contraceptives (Ethinyl Estradiol and Levonorgestrel)

CT

Coadministration of XELJANZ with oral contraceptives had no effect on the PK of either oral contraceptive in healthy females

No dose adjustment is required for either oral contraceptives ethinyl estradiol and levonorgestrel.

Metformin

CT

Coadministration of XELJANZ with metformin, a substrate of Organic Cationic Transporter and Multidrug and Toxic Compound Extrusion, had no effect on the PK of metformin

No dosage adjustment is required for metformin.

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

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 drugs on Pharmacokinetics of Tofacitinib

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

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 results in a decrease in heart rate and an increase in the PR interval (See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests,ADVERSE REACTIONS, Electrocardiography). 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 Biological DMARDs

XELJANZ/XELJANZ XR has not been studied and is not indicated to be used in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators.

Drug-Food Interactions

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

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

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.

Drug-Lifestyle Interactions

No formal studies have been conducted on the effects on the ability to drive and use machines.

Dosage And Administration

Dosing Considerations

There is a risk of added immunosuppression when XELJANZ/ XELJANZ XR is  coadministered with potent immunosuppressive drugs (e.g. azathioprine, tacrolimus, cyclosporine). 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, and selective co-stimulation modulators) has not been studied in rheumatoid arthritis patients and its use should be avoided.

Recommended Doseand Dosage Adjustment

XELJANZ/ XELJANZ XR Posology:
Adults

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

XELJANZ / XELJANZ XR, monotherapy may be considered in cases of intolerance to methotrexate.

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

XELJANZ / XELJANZ XR is given orally with or without food.

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

Switching between XELJANZ Tablets and XELJANZ XR Tablets

Where appropriate, patients treated with XELJANZ 5 mg twice daily 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 twice daily 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, (see WARNINGS AND PRECAUTIONS, Renal; WARNINGS AND PRECAUTIONS, Hepatic and DRUG INTERACTIONS) may be switched to XELJANZ 5 mg once daily, 24 hours following the last dose of XELJANZ XR 11 mg once daily.

Dose Modification due to Serious Infections and Cytopenias (see Tables 3-5 below)

  • It is recommended that XELJANZ/XELJANZ XR not be initiated in patients with an absolute neutrophil count (ANC) less than 1000/mm3, hemoglobin (Hgb) levels < 9 g/d, or with a lymphocyte count less than 500 cells/mm3(see WARNINGS and PRECAUTIONS).
  • Dose interruption is recommended for management of lymphopenia, neutropenia and anemia (see WARNINGS and PRECAUTIONS and ADVERSE REACTIONS).
  • Avoid use of XELJANZ/XELJANZ XR if a patient develops a serious infection until the infections is controlled.
Table 3: Dose Adjustments for Neutropenia

Low ANC

Lab Value

(cells/mm3)

Recommendation

ANC >1000

Maintain dose

ANC 500-1000

For persistent decreases in this range, interrupt administration with XELJANZ/XELJANZ XR until ANC is >1000 cells/mm3


When ANC is >1000 cells/mm3, resume XELJANZ 5 mg BID
 

When ANC is > 1000 cells/mm3, resume XELJANZ XR 11 mg once daily.

 

ANC <500

(Confirmed by repeat testing)

Discontinue treatment with XELJANZ/XELJANZ XR

Table 4: Dose Adjustments for Anemia

Low Hemoglobin Value

Lab Value

(g/dL))

Recommendation

< 2 g/dL decrease and  ≥ 9.0 g/dL

Maintain dose

≥ 2 g/dL decrease or < 8.0 g/dL

(Confirmed by repeat testing)

Interrupt the administration of XELJANZ/XELJANZ XR until hemoglobin values have normalized

Table 5: Dose Adjustments for Lymphopenia Low Lymphocyte Count

Low Lymphocyte Count

Lab Value

(cells/mm3)

Recommendation

Lymphocyte count greater than or equal to 500

Maintain dose

Lymphocyte count less than 500

(Confirmed by repeat testing)

Discontinue XELJANZ/XELJANZ XR

Dose Modification in Patients with Renal or Hepatic Impairment

XELJANZ

  • XELJANZ should not be used in patients with severe hepatic impairment
  • XELJANZ 5 mg once daily is the recommended dose in patients:
    • With moderate (CLcr ≥30 and <60 mL/min) or severe (CLcr ≥15 and <30 mL/min) renal insufficiency, including patients with ESRD undergoing dialysis. Use XELJANZ with Caution in this patient population.
    • With moderate hepatic impairment.

XELJANZ XR

  • XELJANZ XR should not be used in patients with moderate to severe hepatic impairment.
  • 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 ESRD undergoing dialysis.

In patients with moderate hepatic impairment or moderate to severe renal impairment XELJANZ 5 mg once daily may be considered.

Dose Modification due to Drug Interactions

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.

Coadministration of potent inducers of CYP3A4 with XELJANZ/XELJANZ XR is not recommended.

XELJANZ

  • XELJANZ 5 mg once daily is the recommended dose in patients:
    • Receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g ketoconazole).
    • Receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. fluconazole).

XELJANZ XR

  • XELJANZ XR is not recommended in patients
    • Receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g ketoconazole).
    • Receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. fluconazole).

In patients with dose modifications due to drug interactions, XELJANZ 5 mg once daily may be considered.

Special Populations

Geriatrics (>65 years)

No dosage adjustment is required in patients aged 65 years and older (see WARNINGS and PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY section).

Pediatrics(<18 years of age)

The safety and efficacy of XELJANZ/XELJANZ XR in children aged from neonates to less than 18 years of age has not yet been established. Therefore XELJANZ/XELJANZ XR should not be used in this patient population (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY section).

Missed Dose

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

Overdosage

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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action And Clinical Pharmacology

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.

Pharmacodynamics

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 rheumatoid arthritis were small, not dose-dependent and similar to those seen on placebo.

After treatment with XELJANZ in patients with rheumatoid arthritis, 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.

Pharmacokinetics

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.

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 after once daily administration. At steady state, Cmin for XELJANZ XR 11 mg QD is approximately 29% lower and Ctrough is approximately 26% lower compared to XELJANZ 5 mg BID. AUC and Cmax of tofacitinib for XELJANZ XR 11 mg administered once daily are equivalent to those of XELJANZ 5 mg administered twice daily.

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 Cmax 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 Cmax was increased by 27% and Tmax 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.

Excretion:

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.

Table 6: Summary of Tofacitinib Pharmacokinetic Parameters after Repeated Oral Administration of XELJANZ 10 mg BID or Single IV Administration in Humans
 

Oral Administration

IV Administration

 

Cmax

(ng/mL)

t½

(h)

AUC 0-12hrs

(ng·h/mL)

Clearance

(L/h)

Volume of distribution (L)

Healthy Volunteers

79.4

3.0

311

25

87

Patients

116

3.62

507

N/A

(no IV data)

N/A

(no IV data)

N/A = Not available; Cmax = maximum plasma concentration; t½ = terminal elimination half-life; AUC0-12 = area under the plasma concentration-time curve from time 0 to 12 hours post dose; CL = total systemic clearance; Vss = volume of distribution at steady state

Table 7: Summary of Tofacitinib Pharmacokinetic Parameters after Repeated Oral Administration of XELJANZ XR 11 mg QD in Humans
Cmax = maximum plasma concentration; t½ = terminal elimination half-life; AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours post dose
 Cmax
(ng/mL)
t½
(h)
AUC 0-24hrs
(ng·h/mL)

Tmax (h)

Healthy
Volunteers

38.235.89269

4.0

Special Populations and Conditions

Pediatrics (< 18 years of age):

The pharmacokinetics, safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established.

Geriatrics (>65 years of age):

Population PK analysis in rheumatoid arthritis patients indicated that elderly 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%) rheumatoid arthritis patients were 65 years of age and older, including 71 (2%) patients 75 years and older. The frequency of serious infection among XELJANZ treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly (see WARNINGS AND PRECAUTIONS).

Gender

Female patients were estimated to have 7% lower XELJANZ AUC compared to male rheumatoid arthritis patients by population PK analysis.

Race

No major differences (<5%) were observed in XELJANZ AUC between White, Black and Asian patients by population PK analysis. However, there was a higher incidence of adverse events in Asian patients. Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients (see WARNINGS AND PRECAUTIONS).

Body Weight

Population PK analysis in rheumatoid arthritis 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 (Cmax) and lower trough (Cmin) 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%.

Hepatic Impairment:

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 to severe hepatic impairment.

The recommended dose of XELJANZ is 5 mg once daily in patients with moderate hepatic impairment. 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 end-stage renal disease (ESRD) undergoing dialysis, the contribution of dialysis to the total clearance of tofacitinib was relatively small.

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 dialysis.

The recommended dose of XELJANZ is 5 mg once daily in patients with moderate and severe renal impairment including patients with ESRD undergoing dialysis.

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

Genetic Polymorphism:

Mean Cmax 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

* Supplemental doses are not necessary in patients after dialysis
PM=poor metabolizer; PK=Pharmacokinetics; CI=Confidence Interval
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;
Reference group for genetic polymorphism data is extensive metabolizers of CYP2C19.

Storage And Stability

Store between 15°C and 30°C.

Dosage Forms, Composition And Packaging

XELJANZ
Tablet: 5 mg tofacitinib (as tofacitinib citrate) (White to off white round immediate-release film-coated tablets)
HDPE bottles with desiccant and child-resistant caps containing 60 or 180 film-coated tablets.
Foil / foil blisters containing 56 film-coated tablets.

The tablet core contains Croscarmellose Sodium, Lactose Monohydrate, Magnesium Stearate, Microcrystalline Cellulose.  The film coat contains HPMC 2910/Hypromellose 6 cP, Lactose Monohydrate, Macrogol/PEG 3350, Titanium dioxide, Triacetin (Glycerol Triacetate)

XELJANZ XR
Tablets: 11 mg tofacitinib (as tofacitinib citrate) (Pink oval extended-release-coated tablets)
HDPE bottles with desiccant and child-resistant caps containing 14 or 30 extended release film-coated tablets.

The tablet core contains: sorbitol, hydroxyethyl cellulose, copovidone, magnesium stearate. The Film Coat contains cellulose acetate, hydroxypropyl cellulose, HPMC 2910/hypromellose, titanium dioxide, triacetin, red iron oxide. The Printing ink contains shellac glaze, ammonium hydroxide, propylene glycol, ferrosoferric oxide/black iron oxide.

 

 

Control #: 200033
11 December 2017

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