HIGHLIGHTS OF PRESCRIBING INFORMATION
`These 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 use
`Initial U.S. Approval: 2012
`
`WARNING: 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----------------------------
`02/2014
`Indications and Usage (1)
`
`02/2014
`Dosage and Administration (2)
`
`06/2015
`Warnings and Precautions, Serious Infections (5.1)
`
`Warnings and Precautions, Malignancy and Lymphoproliferative
`Disorders (5.2)
`Warnings and Precautions, Laboratory Abnormalities (5.4)
`Warnings and Precautions, Vaccinations (5.5)
`
`03/2014
`
`02/2014
`
`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)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
`1
`INDICATIONS AND USAGE
`1.1 Rheumatoid Arthritis
`2 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 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 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
`
`------------------------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, 8.7, 8.8)
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`Tablets: 5 mg (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------
`None (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)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`The 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)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`
`Revised: 6/2015
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Use in Diabetics
`8.7 Hepatic Impairment
`8.8 Renal Impairment
`10 OVERDOSAGE
`11 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
`
`*Sections or subsections omitted from the Full Prescribing Information
`are not listed.
`
`Reference ID: 3782156
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
`
`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.
`
`Reference ID: 3782156
`
`2
`
`

`

`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.
`Table 1: Dose Adjustments for Lymphopenia
`Low Lymphocyte Count [see Warnings and Precautions (5.4)]
`Recommendation
`
`Lab Value
`(cells/mm3)
`Lymphocyte count greater
`than or equal to 500
`
`Maintain dose
`
`Discontinue XELJANZ
`
`3
`
`Lymphocyte count less than
`500
`
`(Confirmed by repeat testing)
`
`Reference ID: 3782156
`
`

`

`Table 2: Dose Adjustments for Neutropenia
`Low ANC [see Warnings and Precautions (5.4)]
`Recommendation
`
`Lab Value
`(cells/mm3)
`ANC greater than 1000
`
`Maintain dose
`
`ANC 500-1000
`
`For persistent decreases in this range, interrupt dosing until ANC is greater than
`1000
`
`ANC less than 500
`
`(Confirmed by repeat testing)
`
`When ANC is greater than 1000, resume XELJANZ 5 mg twice daily
`Discontinue XELJANZ
`
`Table 3: Dose Adjustments for Anemia
`Low Hemoglobin Value [see Warnings and Precautions (5.4)]
`Recommendation
`
`Lab Value
`(g/dL)
`Less than or equal to 2 g/dL
`decrease and greater than or
`equal to 9.0 g/dL
`
`Maintain dose
`
`Greater than 2 g/dL decrease
`or less than 8.0 g/dL
`
`(Confirmed by repeat testing)
`
`Interrupt the administration of XELJANZ until hemoglobin values have normalized
`
`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).
`
`Reference ID: 3782156
`
`4
`
`

`

`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. The risk of herpes zoster is increased in
`patients treated with XELJANZ and appears to be higher in patients treated with XELJANZ in
`Japan.
`
`Reference ID: 3782156
`
`5
`
`

`

`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).
`
`Reference ID: 3782156
`
`6
`
`

`

`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.
`
`Reference ID: 3782156
`
`7
`
`

`

`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.
`
`Reference ID: 3782156
`
`8
`
`

`

`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.
`
`Reference ID: 3782156
`
`9
`
`

`

`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.
`
`Reference ID: 3782156
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`

`

`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 (3x 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 3x 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 3x 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 3x ULN and bilirubin elevations greater than 2x 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.
`
`Reference ID: 3782156
`
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`

`

`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 Daily*
`
`Preferred Term
`
`Diarrhea
`Nasopharyngitis
`
`Upper respiratory tract infection
`
`Headache
`
`N = 1336
`(%)
`
`4.0
`3.8
`
`4.5
`
`4.3
`
`N = 1349
`(%)
`2.9
`2.8
`
`3.8
`
`3.4
`
`1.6
`Hypertension
`N reflects randomized