XELJANZ

Pfizer Laboratories Div Pfizer Inc

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use XELJANZ safely and effectively. See full prescribing information for XELJANZ. XELJANZ ® (tofacitinib) tablets, for oral useInitial U.S. Approval: 2012BOXED WARNINGWARNING: SERIOUS INFECTIONS AND MALIGNANCY See full prescribing information for complete boxed warning. Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving XELJANZ. (5.1) If a serious infection develops, interrupt XELJANZ until the infection is controlled. (5.1) Prior to starting XELJANZ, perform a test for latent tuberculosis; if it is positive, start treatment for tuberculosis prior to starting XELJANZ. (5.1) Monitor all patients for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative. (5.1) 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. (5.2) RECENT MAJOR CHANGES Indications and Usage (1) 02/2014 Dosage and Administration (2) 02/2014 Warnings and Precautions, Serious Infections (5.1) 03/2014 Warnings and Precautions, Malignancy and Lymphoproliferative Disorders (5.2) 03/2014 Warnings and Precautions, Laboratory Abnormalities (5.4) 02/2014 Warnings and Precautions, Vaccinations (5.5) 02/2014 INDICATIONS AND USAGE XELJANZ is an inhibitor of Janus kinases (JAKs) indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). (1.1) Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.1) DOSAGE AND ADMINISTRATION Rheumatoid Arthritis Recommended dose of XELJANZ is 5 mg twice daily. (2.1) Moderate and severe renal impairment and moderate hepatic impairment: Reduce dose to 5 mg once daily. (2.4, 8.6, 8.7) DOSAGE FORMS AND STRENGTHSTablets: 5 mg (3)CONTRAINDICATIONSNone (4)WARNINGS AND PRECAUTIONS Avoid use of XELJANZ during an active serious infection, including localized infections. (5.1) Gastrointestinal Perforations – Use with caution in patients that may be at increased risk. (5.3) Laboratory Monitoring –Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. (5.4) Immunizations – Live vaccines: Avoid use with XELJANZ. (5.5) Side EffectsThe most commonly reported adverse reactions during the first 3 months in controlled clinical trials (occurring in greater than or equal to 2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, diarrhea and nasopharyngitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole): Reduce dose to 5 mg once daily. (2.3, 7.1) One or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole): Reduce dose to 5 mg once daily. (2.3, 7.2) Potent CYP inducers (e.g., rifampin): May result in loss of or reduced clinical response. (2.3, 7.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 XELJANZ INDICATIONS AND USAGE
  • 1.1 Rheumatoid Arthritis
• 2 XELJANZ DOSAGE AND ADMINISTRATION
  • 2.1 Dosage in Rheumatoid Arthritis
  • 2.2 Dosage Modifications due to Serious Infections and Cytopenias
  • 2.3 Dosage Modifications due to Drug Interactions
  • 2.4 Dosage Modifications in Patients with Renal or Hepatic Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 XELJANZ CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Serious Infections
  • 5.2 Malignancy and Lymphoproliferative Disorders
  • 5.3 Gastrointestinal Perforations
  • 5.4 Laboratory Abnormalities
  • 5.5 Vaccinations
• 6 XELJANZ ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience
• 7 DRUG INTERACTIONS
  • 7.1 Potent CYP3A4 Inhibitors
  • 7.2 Moderate CYP3A4 and Potent CYP2C19 Inhibitors
  • 7.3 Potent CYP3A4 Inducers
  • 7.4 Immunosuppressive Drugs
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
  • 8.7 Renal Impairment
• 10 OVERDOSAGE
• 11 XELJANZ DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• MEDICATION GUIDEXELJANZ (ZEL' JANS')(tofacitinib)
• PRINCIPAL DISPLAY PANEL - 60 Tablet Bottle Label

FULL PRESCRIBING INFORMATION

SERIOUS INFECTIONS

Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ 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 use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].

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 (5.2)].

1 INDICATIONS AND USAGE

1.1 Rheumatoid Arthritis

• XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
• Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Rheumatoid Arthritis

• XELJANZ may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). The recommended dose of XELJANZ is 5 mg twice daily.
• XELJANZ is given orally with or without food.

2.2 Dosage Modifications due to Serious Infections and Cytopenias

(See Tables 1, 2, and 3 below.)

• It is recommended that XELJANZ not be initiated in patients with an absolute lymphocyte count less than 500 cells/mm³, an absolute neutrophil count (ANC) less than 1000 cells/mm³ or who have hemoglobin levels less than 9 g/dL.
• Dose interruption is recommended for management of lymphopenia, neutropenia and anemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
• Avoid use of XELJANZ if a patient develops a serious infection until the infection is controlled.

2.3 Dosage Modifications due to Drug Interactions

• XELJANZ dosage should be reduced to 5 mg once daily 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).
• Coadministration of potent inducers of CYP3A4 (e.g., rifampin) with XELJANZ may result in loss of or reduced clinical response to XELJANZ. Coadministration of potent inducers of CYP3A4 with XELJANZ is not recommended.

2.4 Dosage Modifications in Patients with Renal or Hepatic Impairment

• XELJANZ dosage should be reduced to 5 mg once daily in patients:
  • with moderate or severe renal insufficiency.
  • with moderate hepatic impairment.
• Use of XELJANZ in patients with severe hepatic impairment is not recommended.

3 DOSAGE FORMS AND STRENGTHS

XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Serious 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 XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus 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., histoplasmosis, coccidioidomycosis, and listeriosis).

Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients:

• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled 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 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 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.

Tuberculosis

Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ.

Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ 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 who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

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.

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

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 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.

5.2 Malignancy and Lymphoproliferative Disorders

Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ [see Adverse Reactions (6.1)].

In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ.

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

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

5.3 Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known.

XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., 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 (6.1)].

5.4 Laboratory Abnormalities

Lymphocyte Abnormalities

Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute 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 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 treatment with XELJANZ is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts see Dosage and Administration (2.2) .

Neutropenia

Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm³) compared to placebo.

Avoid initiation of XELJANZ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm³). For patients who develop a persistent ANC of 500–1000 cells/mm³, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm³. In patients who develop an ANC less than 500 cells/mm³, treatment with XELJANZ is not recommended.

Monitor neutrophil counts at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results see Dosage and Administration (2.2) .

Anemia

Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results see Dosage and Administration (2.2) .

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 tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ 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 approximately 4–8 weeks following initiation of XELJANZ therapy.

Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

5.5 Vaccinations

No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. Avoid use of live vaccines concurrently with XELJANZ.

Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily.

The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. 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.

The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)].

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections

In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections

In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1)].

Tuberculosis

In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily 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 (5.1)].

Opportunistic Infections (excluding tuberculosis)

In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) [see Warnings and Precautions (5.1)].

Malignancy

In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, 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 (5.2)].

Laboratory Abnormalities

Lymphopenia

In the controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm³ occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 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 (5.4)].

Neutropenia

In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm³ occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/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 trials [see Warnings and Precautions (5.4)].

Liver Enzyme Elevations

Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients treated with XELJANZ. 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 monotherapy trials (0–3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

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

Lipid Elevations

In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below:

• Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
• Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
• Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

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

Serum Creatinine Elevations

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.

Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.

Table 4: Adverse Reactions Occurring in at Least 2% or More of Patients on 5 or 10 mg Twice Daily XELJANZ With or Without DMARD (0–3 months) and at Least 1% Greater Than That Observed in Patients on Placebo

	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice DailyThe recommended dose of XELJANZ is 5 mg twice daily.	Placebo
Preferred Term	N = 1336 (%)	N = 1349 (%)	N = 809 (%)
N reflects randomized and treated patients from the seven clinical trials
Diarrhea	4.0	2.9	2.3
Nasopharyngitis	3.8	2.8	2.8
Upper respiratory tract infection	4.5	3.8	3.3
Headache	4.3	3.4	2.1
Hypertension	1.6	2.3	1.1

Other adverse reactions occurring in controlled and open-label extension studies included:

Blood and lymphatic system disorders: Anemia

Metabolism and nutrition disorders: Dehydration

Psychiatric disorders: Insomnia

Nervous system disorders: Paresthesia

Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion

Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea

Hepatobiliary disorders: Hepatic steatosis

Skin and subcutaneous tissue disorders: Rash, erythema, pruritus

Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling

Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers

General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema

Clinical Experience in Methotrexate-Naïve Patients

Study VI was an active-controlled clinical trial in methotrexate-naïve patients [see Clinical Studies (14)]. The safety experience in these patients was consistent with Studies I–V.

7 DRUG INTERACTIONS

7.1 Potent CYP3A4 Inhibitors

Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole) [see Dosage and Administration (2.3) and Figure 3].

7.2 Moderate CYP3A4 and Potent CYP2C19 Inhibitors

Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) [see Dosage and Administration (2.3) and Figure 3].

7.3 Potent CYP3A4 Inducers

Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin) [see Dosage and Administration (2.3) and Figure 3].

7.4 Immunosuppressive Drugs

There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressants has not been studied in rheumatoid arthritis. Use of XELJANZ in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic effects:

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).

In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).

Nonteratogenic effects:

In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).

Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

8.3 Nursing Mothers

Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric Use

The safety and effectiveness of XELJANZ in pediatric patients have not been established.

8.5 Geriatric Use

Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. 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. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

8.6 Hepatic Impairment

XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib levels than XELJANZ-treated patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Higher blood levels may increase the risk of some adverse reactions, therefore, XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment [see Dosage and Administration (2.4)]. XELJANZ has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and efficacy of XELJANZ have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

8.7 Renal Impairment

XELJANZ-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than XELJANZ-treated patients with normal renal function; therefore, XELJANZ dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment [see Dosage and Administration (2.4)]. In clinical trials, XELJANZ was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min. No dose adjustment is required in patients with mild renal impairment.

10 OVERDOSAGE

Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans

There is no experience with overdose of XELJANZ.

Treatment or Management of Overdose

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

There is no specific antidote for overdose with XELJANZ. 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.

11 DESCRIPTION

XELJANZ is the citrate salt of tofacitinib, a JAK inhibitor.

Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) .

The solubility of tofacitinib citrate in water is 2.9 mg/mL.

Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C₁₆H₂₀N₆O•C₆H₈O₇. The chemical structure of tofacitinib citrate is:

XELJANZ is supplied for oral administration as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) white round, immediate-release film-coated tablet. Each tablet of XELJANZ contains the appropriate amount of XELJANZ as a citrate salt and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, HPMC 2910/Hypromellose 6cP, titanium dioxide, macrogol/PEG3350, and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC₅₀ of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

12.2 Pharmacodynamics

Treatment with XELJANZ 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 (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.

Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.

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 pharmacokinetic half-life.

12.3 Pharmacokinetics

Following oral administration of XELJANZ, peak plasma concentrations are reached within 0.5–1 hour, elimination half-life is ~3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24–48 hours with negligible accumulation after twice daily administration.

Absorption

The absolute oral bioavailability of tofacitinib is 74%. 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 meals.

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 and Elimination

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.

Pharmacokinetics in Rheumatoid Arthritis Patients

Population PK analysis in rheumatoid arthritis patients indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). 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 tofacitinib is estimated to be approximately 27%.

Specific Populations

The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.

Figure 1: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics

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.

Drug Interactions

Potential for XELJANZ to Influence the PK of Other Drugs

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 C_max of a 5 mg twice daily dose. These 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 arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.

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 low.

Dosing recommendations for coadministered drugs following administration with XELJANZ are shown in Figure 2.

Figure 2. Impact of XELJANZ on PK of Other Drugs

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

Potential for Other Drugs to Influence the PK of Tofacitinib

Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the PK of tofacitinib. Dosing recommendations for XELJANZ for administration with CYP inhibitors or inducers are shown in Figure 3.

Figure 3. Impact of Other Drugs on PK of XELJANZ

Note: Reference group is administration of tofacitinib alone

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the MRHD (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the MRHD (on an AUC basis at oral doses of 1 mg/kg twice daily).

The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the MRHD (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.

In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the MRHD on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.

Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.

In rats, tofacitinib at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the MRHD (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.

14 CLINICAL STUDIES

The XELJANZ clinical development program included two dose-ranging trials and five confirmatory trials. Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily.

DOSE-RANGING TRIALS

Dose selection for XELJANZ was based on two pivotal dose-ranging trials.

Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: XELJANZ 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by XELJANZ 5 mg twice daily for 3 months, or placebo.

Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of XELJANZ (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.

The results of XELJANZ-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and XELJANZ 1 mg groups compared to patients treated with the other XELJANZ doses. However, there was no difference in the proportion of responders among patients treated with XELJANZ 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.

Figure 4: Proportion of Patients with ACR20 Response at Month 3 in Dose-Ranging Studies 1 and 2

Study 1 was a dose-ranging monotherapy trial not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority to adalimumab.

CONFIRMATORY TRIALS

Study I was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.

Study II was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.

Study III was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

Study IV was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

Study V was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.

Study VI was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active rheumatoid arthritis received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.

Clinical Response

The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, IV, and V are shown in Table 5. Similar results were observed with Studies II and III. In trials I–V, patients treated with either 5 or 10 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.

Table 5: Proportion of Patients with an ACR Response

	Percent of Patients
	Monotherapy in Nonbiologic or Biologic DMARD Inadequate RespondersInadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity.			MTX Inadequate RespondersInadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria.			TNF Inhibitor Inadequate RespondersInadequate response to a least one TNF inhibitor due to lack of efficacy and/or intolerance.
	Study I			Study IV			Study V
NN is number of randomized and treated patients.	PBO	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice DailyThe recommended dose of XELJANZ is 5 mg twice daily.	PBO + MTX	XELJANZ 5 mg Twice Daily + MTX	XELJANZ 10 mg Twice Daily + MTXThe recommended dose of XELJANZ is 5 mg twice daily.	PBO + MTX	XELJANZ 5 mg Twice Daily + MTX	XELJANZ 10 mg Twice Daily + MTXThe recommended dose of XELJANZ is 5 mg twice daily.
	122	243	245	160	321	316	132	133	134
ACR20
Month 3	26%	59%	65%	27%	55%	67%	24%	41%	48%
Month 6	NANA Not applicable, as data for placebo treatment is not available beyond 3 months in Studies I and V due to placebo advancement.	69%	70%	25%	50%	62%	NA	51%	54%
ACR50
Month 3	12%	31%	36%	8%	29%	37%	8%	26%	28%
Month 6	NA	42%	46%	9%	32%	44%	NA	37%	30%
ACR70
Month 3	6%	15%	20%	3%	11%	17%	2%	14%	10%
Month 6	NA	22%	29%	1%	14%	23%	NA	16%	16%

In Study IV, a greater proportion of patients treated with XELJANZ 5 mg or 10 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 6).

Table 6: Proportion of Patients with DAS28-4(ESR) Less Than 2.6 with Number of Residual Active Joints

Study IV
DAS28-4(ESR) Less Than 2.6	Placebo + MTX	XELJANZ 5 mg Twice Daily + MTX	XELJANZ 10 mg Twice Daily + MTXThe recommended dose of XELJANZ is 5 mg twice daily.
	160	321	316
Proportion of responders at Month 6 (n)	1% (2)	6% (19)	13% (42)
Of responders, proportion with 0 active joints (n)	50% (1)	42% (8)	36% (15)
Of responders, proportion with 1 active joint (n)	0	5% (1)	17% (7)
Of responders, proportion with 2 active joints (n)	0	32% (6)	7% (3)
Of responders, proportion with 3 or more active joints (n)	50% (1)	21% (4)	40% (17)

The results of the components of the ACR response criteria for Study IV are shown in Table 7. Similar results were observed for XELJANZ in Studies I, II, III, V, and VI.

Table 7: Components of ACR Response at Month 3

	Study IV
	XELJANZ 5 mg Twice Daily + MTX		XELJANZ 10 mgThe recommended dose of XELJANZ is 5 mg twice daily. Twice Daily + MTX		Placebo + MTX
	N=321		N=316		N=160
Component (mean) Data shown is mean (Standard Deviation) at Month 3.	Baseline	Month 3Data shown is mean (Standard Deviation) at Month 3.	Baseline	Month 3Data shown is mean (Standard Deviation) at Month 3.	Baseline	Month 3Data shown is mean (Standard Deviation) at Month 3.
Number of tender joints (0–68)	24 (14)	13 (14)	23 (15)	10 (12)	23 (13)	18 (14)
Number of swollen joints (0–66)	14 (8)	6 (8)	14 (8)	6 (7)	14 (9)	10 (9)
PainVisual analog scale: 0 = best, 100 = worst.	58 (23)	34 (23)	58 (24)	29 (22)	55 (24)	47 (24)
Patient global assessmentVisual analog scale: 0 = best, 100 = worst.	58 (24)	35 (23)	57 (23)	29 (20)	54 (23)	47 (24)
Disability index (HAQ-DI)Health Assessment Questionnaire Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.	1.41 (0.68)	0.99 (0.65)	1.40 (0.66)	0.84 (0.64)	1.32 (0.67)	1.19 (0.68)
Physician global assessmentVisual analog scale: 0 = best, 100 = worst.	59 (16)	30 (19)	58 (17)	24 (17)	56 (18)	43 (22)
CRP (mg/L)	15.3 (19.0)	7.1 (19.1)	17.1 (26.9)	4.4 (8.6)	13.7 (14.9)	14.6 (18.7)

The percent of ACR20 responders by visit for Study IV is shown in Figure 5. Similar responses were observed for XELJANZ in Studies I, II, III, V, and VI.

Figure 5: Percentage of ACR20 Responders by Visit for Study IV

Radiographic Response

Two studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study IV and Study VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.

In Study IV, XELJANZ 10 mg twice daily plus background MTX reduced the progression of structural damage compared to placebo plus MTX at Month 6. When given at a dose of 5 mg twice daily, XELJANZ exhibited similar effects on mean progression of structural damage (not statistically significant). These results are shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% and 79% of patients treated with XELJANZ plus MTX 5 or 10 mg twice daily.

In Study VI, XELJANZ monotherapy inhibited the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the MTX group, 55% of patients experienced no radiographic progression at Month 6 compared to 73% and 77% of patients treated with XELJANZ 5 or 10 mg twice daily.

Table 8: Radiographic Changes at Months 6 and 12

	Study IV
	Placebo	XELJANZ 5 mg Twice Daily	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice DailyThe recommended dose of XELJANZ is 5 mg twice daily.	XELJANZ 10 mg Twice Daily
	N=139 Mean (SD)SD = Standard Deviation	N=277 Mean (SD) SD = Standard Deviation	Mean Difference from PlaceboDifference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval) (CI)	N=290 Mean (SD) SD = Standard Deviation	Mean Difference from PlaceboDifference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval) (CI)
mTSS Month 6 and Month 12 data are mean change from baseline.
Baseline	33 (42)	31 (48)	-	37 (54)	-
Month 6	0.5 (2.0)	0.1 (1.7)	-0.3 (-0.7, 0.0)	0.1 (2.0)	-0.4 (-0.8, 0.0)
	Study VI
	MTX	XELJANZ 5 mg Twice Daily	XELJANZ 5 mg Twice Daily	XELJANZ 10 mg Twice DailyThe recommended dose of XELJANZ is 5 mg twice daily.	XELJANZ 10 mg Twice Daily
	N=166 Mean (SD)SD = Standard Deviation	N=346 Mean (SD) SD = Standard Deviation	Mean Difference from MTXDifference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval) (CI)	N=369 Mean (SD) SD = Standard Deviation	Mean Difference from MTXDifference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval) (CI)
mTSSMonth 6 and Month 12 data are mean change from baseline.
Baseline	17 (29)	20 (40)	-	19 (39)	-
Month 6	0.8 (2.7)	0.2 (2.3)	-0.7 (-1.0, -0.3)	0.0 (1.2)	-0.8 (-1.2, -0.4)
Month 12	1.3 (3.7)	0.4 (3.0)	-0.9 (-1.4, -0.4)	0.0 (1.5)	-1.3 (-1.8, -0.8)

Physical Function Response

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 and 10 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.

The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study III was -0.22 (-0.35, -0.10) in patients receiving 5 mg XELJANZ twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg XELJANZ twice daily. Similar results were obtained in Studies I, II, IV and V. In the 12-month trials, HAQ-DI results in XELJANZ-treated patients were consistent at 6 and 12 months.

Other Health-Related Outcomes

General health status was assessed by the Short Form health survey (SF-36). In studies I, IV, and V, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.

16 HOW SUPPLIED/STORAGE AND HANDLING

XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side, and available in:

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature].

Do not repackage.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patient Counseling

Advise patients of the potential benefits and risks of XELJANZ.

Serious Infection

Inform patients that XELJANZ may lower the ability of their immune system to fight infections. Advise patients not to start taking XELJANZ if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order to ensure rapid evaluation and appropriate treatment [see Warnings and Precautions (5.1)].

Malignancies and Lymphoproliferative Disorders

Inform patients that XELJANZ may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking XELJANZ. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions (5.2)].

Important Information on Laboratory Abnormalities

Inform patients that XELJANZ may affect certain lab test results, and that blood tests are required before and during XELJANZ treatment [see Warnings and Precautions (5.4)].

Pregnancy

Inform patients that XELJANZ should not be used during pregnancy unless clearly necessary, and advise patients to inform their doctors right away if they become pregnant while taking XELJANZ. Inform patients that Pfizer has a registry for pregnant women who have taken XELJANZ during pregnancy. Advise patients to contact the registry at 1-877-311-8972 to enroll [see Pregnancy (8.1)].

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

LAB-0445-7.0

MEDICATION GUIDEXELJANZ (ZEL' JANS')(tofacitinib)

Read this Medication Guide before you start taking XELJANZ and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about XELJANZ?

XELJANZ may cause serious side effects including:

1. Serious infections.

XELJANZ is a medicine that affects your immune system. XELJANZ can lower the ability of your immune system to fight infections. Some people have serious infections while taking XELJANZ, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections.

• Your healthcare provider should test you for TB before starting XELJANZ.
• Your healthcare provider should monitor you closely for signs and symptoms of TB infection during treatment with XELJANZ.

You should not start taking XELJANZ if you have any kind of infection unless your healthcare provider tells you it is okay.

Before starting XELJANZ, tell your healthcare provider if you:

• think you have an infection or have symptoms of an infection such as:

  fever, sweating, or chills muscle aches cough shortness of breath blood in phlegm weight loss

  warm, red, or painful skin or sores on your body diarrhea or stomach pain burning when you urinate or urinating more often than normal feeling very tired

• are being treated for an infection
• get a lot of infections or have infections that keep coming back
• have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections.
• have TB, or have been in close contact with someone with TB
• live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you use XELJANZ. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.
• have or have had hepatitis B or C

After starting XELJANZ, call your healthcare provider right away if you have any symptoms of an infection. XELJANZ can make you more likely to get infections or make worse any infection that you have.

2. Cancer and immune system problems.

XELJANZ may increase your risk of certain cancers by changing the way your immune system works.

• Lymphoma and other cancers including skin cancers can happen in patients taking XELJANZ. Tell your healthcare provider if you have ever had any type of cancer.
• Some people who have taken XELJANZ with certain other medicines to prevent kidney transplant rejection have had a problem with certain white blood cells growing out of control (Epstein Barr Virus-associated post transplant lymphoproliferative disorder).

3. Tears (perforation) in the stomach or intestines.

• Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking XELJANZ get tears in their stomach or intestine. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate.
• Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits.

4. Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start receiving XELJANZ and while you take XELJANZ to check for the following side effects:

• changes in lymphocyte counts. Lymphocytes are white blood cells that help the body fight off infections.
• low neutrophil counts. Neutrophils are white blood cells that help the body fight off infections.
• low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired.

Your healthcare provider should routinely check certain liver tests.

You should not receive XELJANZ if your lymphocyte count, neutrophil count, or red blood cell count is too low or your liver tests are too high.

Your healthcare provider may stop your XELJANZ treatment for a period of time if needed because of changes in these blood test results.

You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start receiving XELJANZ, and as needed after that. Normal cholesterol levels are important to good heart health.

See "What are the possible side effects of XELJANZ?" for more information about side effects.

What is XELJANZ?

XELJANZ is a prescription medicine called a Janus kinase (JAK) inhibitor. XELJANZ is used to treat adults with moderately to severely active rheumatoid arthritis in which methotrexate did not work well.

It is not known if XELJANZ is safe and effective in people with Hepatitis B or C.

XELJANZ is not for people with severe liver problems.

It is not known if XELJANZ is safe and effective in children.

What should I tell my healthcare provider before taking XELJANZ?

XELJANZ may not be right for you. Before taking XELJANZ, tell your healthcare provider if you:

• have an infection. See "What is the most important information I should know about XELJANZ?"
• have liver problems
• have kidney problems
• have any stomach area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines
• have had a reaction to tofacitinib or any of the ingredients in XELJANZ
• have recently received or are scheduled to receive a vaccine. People who take XELJANZ should not receive live vaccines. People taking XELJANZ can receive non-live vaccines.
• have any other medical conditions
• plan to become pregnant or are pregnant. It is not known if XELJANZ will harm an unborn baby.

  Pregnancy Registry: Pfizer has a registry for pregnant women who take XELJANZ. The purpose of this registry is to check the health of the pregnant mother and her baby. If you are pregnant or become pregnant while taking XELJANZ, talk to your healthcare provider about how you can join this pregnancy registry or you may contact the registry at 1-877-311-8972 to enroll.

• plan to breastfeed or are breastfeeding. You and your healthcare provider should decide if you will take XELJANZ or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. XELJANZ and other medicines may affect each other causing side effects.

Especially tell your healthcare provider if you take:

• any other medicines to treat your rheumatoid arthritis. You should not take tocilizumab (Actemra^®), etanercept (Enbrel^®), adalimumab (Humira^®), infliximab (Remicade^®), rituximab (Rituxan^®), abatacept (Orencia^®), anakinra (Kineret^®), certolizumab (Cimzia^®), golimumab (Simponi^®), azathioprine, cyclosporine, or other immunosuppressive drugs while you are taking XELJANZ. Taking XELJANZ with these medicines may increase your risk of infection.
• medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take XELJANZ?

• Take XELJANZ as your healthcare provider tells you to take it.
• Take XELJANZ 2 times a day with or without food.
• If you take too much XELJANZ, call your healthcare provider or go to the nearest hospital emergency room right away.

What are possible side effects of XELJANZ?

XELJANZ may cause serious side effects, including:

• See "What is the most important information I should know about XELJANZ?"
• Hepatitis B or C activation infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B or C virus (viruses that affect the liver), the virus may become active while you use XELJANZ. Your healthcare provider may do blood tests before you start treatment with XELJANZ and while you are using XELJANZ. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B or C infection:

  feel very tired skin or eyes look yellow little or no appetite vomiting clay-colored bowel movements

  fevers chills stomach discomfort muscle aches dark urine skin rash

Common side effects of XELJANZ include:

• upper respiratory tract infections (common cold, sinus infections)
• headache
• diarrhea
• nasal congestion, sore throat, and runny nose (nasopharyngitis)

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of XELJANZ. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Pfizer at 1-800-438-1985.

How should I store XELJANZ?

Store XELJANZ at 68°F to 77°F (room temperature).

Safely throw away medicine that is out of date or no longer needed.

Keep XELJANZ and all medicines out of the reach of children.

General information about the safe and effective use of XELJANZ.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XELJANZ for a condition for which it was not prescribed. Do not give XELJANZ to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about XELJANZ. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about XELJANZ that is written for health professionals.

What are the ingredients in XELJANZ?

Active ingredient: tofacitinib citrate

Inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, HPMC 2910/Hypromellose 6cP, titanium dioxide, macrogol/PEG3350, and triacetin.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

LAB-0535-2.0
March 2014

PRINCIPAL DISPLAY PANEL - 60 Tablet Bottle Label

ALWAYS DISPENSE WITH
MEDICATION GUIDE

Pfizer

NDC 0069-1001-01

Xeljanz™
(tofacitinib tablets)

5 mg*

60 Tablets

Rx only