HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`XELJANZ/XELJANZ XR safely and effectively. See full prescribing
`information for XELJANZ.
`
`XELJANZ ® (tofacitinib) tablets, for oral use
`XELJANZ ® XR (tofacitinib) extended release 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/XELJANZ XR
`until the infection is controlled. (5.1)
` Prior to starting XELJANZ/XELJANZ XR, perform a test for latent
`tuberculosis; if it is positive, start treatment for tuberculosis prior to
`starting XELJANZ/XELJANZ XR. (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----------------------------
`Warnings and Precautions, Serious Infections (5.1)
`8/2017
`Warnings and Precautions, Malignancy and
`Lymphoproliferative Disorders (5.2)
`Warnings and Precautions, Vaccinations (5.5)
`
`8/2017
`8/2017
`
`---------------------------INDICATIONS AND USAGE----------------------------
` XELJANZ/XELJANZ XR 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/XELJANZ XR 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)
` Recommended dose of XELJANZ XR is 11 mg once daily. (2.1)
` Recommended dose in patients with moderate and severe renal
`impairment and moderate hepatic impairment is XELJANZ 5 mg once
`
`daily. (2.4, 8.6, 8.7)
`
` Use of XELJANZ/XELJANZ XR in patients with severe hepatic
`
`impairment is not recommended. (2.4, 8.7)
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`XELJANZ Tablets: 5 mg (3)
`
`XELJANZ XR Tablets: 11 mg (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------
`None (4)
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
` Avoid use of XELJANZ/XELJANZ XR 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/XELJANZ
`
`XR. (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):
`Recommended dose is XELJANZ 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):
`
`Recommended dose is XELJANZ 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: 8/2017
`
`Reference ID: 4142642
`
`

`

`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
`
`Dosage Modifications in Patients with Renal or Hepatic
`
`2.4
`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
`
`5.6
`General
`
`6 ADVERSE REACTIONS
`6.1
`Clinical Trial Experience
`
`7 DRUG INTERACTIONS
`7.1
`Potent CYP3A4 Inhibitors
`
`7.2 Moderate CYP3A4 and Potent CYP2C19 Inhibitors
`
`
`Potent CYP3A4 Inducers
`
`7.3
`Immunosuppressive Drugs
`
`7.4
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`8.2
`Lactation
`
`8.3
`Females and Males of Reproductive Potential
`
`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: 4142642
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
`
`SERIOUS INFECTIONS
`Patients treated with XELJANZ/XELJANZ XR 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/XELJANZ XR until the infection is
`controlled.
`
`Reported infections include:
`
`• Active tuberculosis, which may present with pulmonary or extrapulmonary disease.
`Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use
`and during therapy. Treatment for latent infection should be initiated prior to
`XELJANZ/XELJANZ XR use.
`• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with
`invasive fungal infections may present with disseminated, rather than localized, disease.
`• Bacterial, viral, and other infections due to opportunistic pathogens.
`The risks and benefits of treatment with XELJANZ/XELJANZ XR 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/XELJANZ XR, 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/XELJANZ XR (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).
`
`Reference ID: 4142642
`
`3
`
`

`

` Limitations of Use: Use of XELJANZ/XELJANZ XR 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/XELJANZ XR 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 and the recommended dose of XELJANZ XR is
`11 mg once daily.
`
` XELJANZ/XELJANZ XR is given orally with or without food.
`
` Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.
`
`Switching from XELJANZ Tablets to XELJANZ XR Tablets
`Patients treated with XELJANZ 5 mg twice daily may be switched to XELJANZ XR 11 mg once
`daily the day following the last dose of XELJANZ 5 mg.
`
`2.2 Dosage Modifications due to Serious Infections and Cytopenias (see Tables 1, 2, and 3
`below)
`It is recommended that XELJANZ/XELJANZ XR 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/XELJANZ XR if a patient develops a serious infection until the
`infection is controlled.
`
`2.3 Dosage Modifications due to Drug Interactions
`In patients receiving:
`
` potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole), or
` one or more concomitant medications that result in both moderate inhibition of CYP3A4
`and potent inhibition of CYP2C19 (e.g., fluconazole),
`the recommended dose is XELJANZ 5 mg once daily.
` Coadministration of potent inducers of CYP3A4 (e.g., rifampin) with XELJANZ/XELJANZ
`XR may result in loss of or reduced clinical response to XELJANZ/XELJANZ XR.
` Coadministration of potent inducers of CYP3A4 with XELJANZ/XELJANZ XR is not
`recommended.
`
`2.4 Dosage Modifications in Patients with Renal or Hepatic Impairment
`In patients with:
`
` moderate or severe renal insufficiency, or
` moderate hepatic impairment,
`the recommended dose is XELJANZ 5 mg once daily.
`
`4
`
`Reference ID: 4142642
`
`

`

` Use of XELJANZ/XELJANZ XR 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
`
`Lymphocyte count less than
`500
`
`(Confirmed by repeat testing)
`
`Maintain dose
`
`Discontinue XELJANZ/XELJANZ XR
`
`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
`
`When ANC is greater than 1000, resume XELJANZ 5 mg twice daily/XELJANZ
`XR 11 mg once daily
`Discontinue XELJANZ/XELJANZ XR
`
`ANC less than 500
`
`(Confirmed by repeat testing)
`
`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
`Greater than 2 g/dL decrease
`or less than 8.0 g/dL
`
`Maintain dose
`
`Interrupt the administration of XELJANZ/XELJANZ XR until hemoglobin values
`have normalized
`
`(Confirmed by repeat testing)
`
`Reference ID: 4142642
`
`5
`
`

`

`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.
`
`XELJANZ XR is provided as 11 mg tofacitinib (equivalent to 17.77 mg tofacitinib citrate)
`tablets: Pink, oval, extended release film-coated tablets with a drilled hole at one end of the tablet
`band and “JKI 11” printed on one side of the tablet.
`
`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, urinary tract infection, diverticulitis, and appendicitis. Among
`opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis,
`esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus
`infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have
`presented with disseminated rather than localized disease, and were often taking concomitant
`immunomodulating agents such as methotrexate or corticosteroids.
`
`Other serious infections that were not reported in clinical studies may also occur (e.g.,
`histoplasmosis and coccidioidomycosis).
`
`Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including
`localized infections. The risks and benefits of treatment should be considered prior to initiating
`XELJANZ/XELJANZ XR in patients:
`• with chronic or recurrent 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 XR. XELJANZ/XELJANZ XR should be
`interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A
`patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should
`undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient;
`appropriate antimicrobial therapy should be initiated, and the patient should be closely
`monitored.
`
`6
`
`Reference ID: 4142642
`
`

`

`Caution is also recommended in patients with a history of chronic lung disease, or in those who
`develop interstitial lung disease, as they may be more prone to infections.
`
`Risk of infection may be higher with increasing degrees of lymphopenia and consideration
`should be given to lymphocyte counts when assessing individual patient risk of infection.
`Discontinuation and monitoring criteria for lymphopenia are discussed in Dosage Modifications
`due to Serious Infections and Cytopenias [see Dosage and Administration (2.2)].
`
`Tuberculosis
`Patients should be evaluated and tested for latent or active infection prior to and per applicable
`guidelines during administration of XELJANZ /XELJANZ XR.
`
`Anti-tuberculosis therapy should also be considered prior to administration of
`XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom
`an adequate course of treatment cannot be confirmed, and for patients with a negative test for
`latent tuberculosis but 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/XELJANZ XR.
`
`Viral Reactivation
`Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were
`observed in clinical studies with XELJANZ. The impact of XELJANZ/XELJANZ XR on
`chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or
`C were excluded from clinical trials. Screening for viral hepatitis should be performed in
`accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The
`risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears
`to be higher in patients treated with XELJANZ in Japan and Korea.
`
`5.2 Malignancy and Lymphoproliferative Disorders
`Consider the risks and benefits of XELJANZ/XELJANZ XR 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/XELJANZ XR 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.
`
`Reference ID: 4142642
`
`7
`
`

`

`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.
`
`Other malignancies were observed in clinical studies and the post-marketing setting, including,
`but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
`
`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/XELJANZ XR 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/XELJANZ XR treatment in patients with a low lymphocyte count
`(i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count
`less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR 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/XELJANZ XR 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/XELJANZ XR dosing until ANC is greater than or
`
`Reference ID: 4142642
`
`8
`
`

`

`equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment
`with XELJANZ/XELJANZ XR 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/XELJANZ XR treatment in patients with a low hemoglobin level
`(i.e. less than 9 g/dL). Treatment with XELJANZ/XELJANZ XR 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/XELJANZ XR 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/XELJANZ XR therapy.
`
`Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program
`(NCEP)] for the management of hyperlipidemia.
`
`5.5 Vaccinations
`
`Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between
`live vaccinations and initiation of tofacitinib therapy should be in accordance with current
`vaccination guidelines regarding immunosuppressive agents.
`
`Reference ID: 4142642
`
`9
`
`

`

`A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after
`vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with
`tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous
`history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was
`discontinued and the patient recovered after treatment with standard doses of antiviral
`medication.
`
`Update immunizations in agreement with current immunization guidelines prior to initiating
`XELJANZ/XELJANZ XR therapy.
`
`5.6 General
`
`Specific to XELJANZ XR
`As with any other non-deformable material, caution should be used when administering
`XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or
`iatrogenic). There have been rare reports of obstructive symptoms in patients with known
`strictures in association with the ingestion of other drugs utilizing a non-deformable extended
`release formulation.
`
`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.
`
`The clinical studies described in the following sections were conducted using XELJANZ.
`Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is
`5 mg twice daily.
`
`The recommended dose for XELJANZ XR is 11 mg once 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
`
`Reference ID: 4142642
`
`10
`
`

`

`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)].
`
`Reference ID: 4142642
`
`11
`
`

`

`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.
`
`Reference ID: 4142642
`
`12
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`

`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 (3x ULN)
`were observed in patients treated