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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` XELJANZ safely and effectively. See full prescribing information for
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` XELJANZ.
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`XELJANZ® (tofacitinib) tablets, for oral use
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`Initial U.S. Approval: 2012
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`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
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`See full prescribing information for complete boxed warning.
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` Serious infections leading to hospitalization or death, including
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`tuberculosis and bacterial, invasive fungal, viral, and other
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`opportunistic infections, have occurred in patients receiving
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`XELJANZ. (5.1)
` If a serious infection develops, interrupt XELJANZ until the infection
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`is controlled. (5.1)
` Prior to starting XELJANZ, perform a test for latent tuberculosis; if
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`it is positive, start treatment for tuberculosis prior to starting
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`XELJANZ. (5.1)
` Monitor all patients for active tuberculosis during treatment, even if
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`the initial latent tuberculosis test is negative. (5.1)
` Lymphoma and other malignancies have been observed in patients
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`treated with XELJANZ. Epstein Barr Virus-associated post-
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`transplant lymphoproliferative disorder has been observed at an
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`increased rate in renal transplant patients treated with XELJANZ
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`and concomitant immunosuppressive medications. (5.2)
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`--------------------------RECENT MAJOR CHANGES---------------------------­
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`Warnings and Precautions, Serious Infections (5.1)
`6/2015
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`---------------------------INDICATIONS AND USAGE---------------------------­
` XELJANZ is an inhibitor of Janus kinases (JAKs) indicated for the
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`treatment of adult patients with moderately to severely active rheumatoid
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`arthritis who have had an inadequate response or intolerance to
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`methotrexate. It may be used as monotherapy or in combination with
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`methotrexate or other nonbiologic disease-modifying antirheumatic drugs
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`(DMARDs). (1.1)
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` Limitations of Use: Use of XELJANZ in combination with biologic
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`DMARDs or potent immunosuppressants such as azathioprine and
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`cyclosporine is not recommended. (1.1)
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
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`INDICATIONS AND USAGE
`1
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`1.1 Rheumatoid Arthritis
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Dosage in Rheumatoid Arthritis
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`2.2 Dosage Modifications due to Serious Infections and Cytopenias
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`2.3 Dosage Modifications due to Drug Interactions
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`2.4 Dosage Modifications in Patients with Renal or Hepatic
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`Impairment
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`3 DOSAGE FORMS AND STRENGTHS
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`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Serious Infections
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`5.2 Malignancy and Lymphoproliferative Disorders
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`5.3 Gastrointestinal Perforations
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`5.4 Laboratory Abnormalities
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`5.5 Vaccinations
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trial Experience
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`7 DRUG INTERACTIONS
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`7.1 Potent CYP3A4 Inhibitors
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`7.2 Moderate CYP3A4 and Potent CYP2C19 Inhibitors
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`7.3 Potent CYP3A4 Inducers
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`7.4 Immunosuppressive Drugs
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`Reference ID: 3864584
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`------------------------DOSAGE AND ADMINISTRATION---------------------­
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`Rheumatoid Arthritis
` Recommended dose of XELJANZ is 5 mg twice daily. (2.1)
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` Moderate and severe renal impairment and moderate hepatic impairment:
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`Reduce dose to 5 mg once daily. (2.4, 8.7, 8.8)
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`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
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`Tablets: 5 mg (3)
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`-------------------------------CONTRAINDICATIONS----------------------------­
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`None (4)
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`------------------------WARNINGS AND PRECAUTIONS----------------------­
` Avoid use of XELJANZ during an active serious infection, including
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`localized infections. (5.1)
` Gastrointestinal Perforations – Use with caution in patients that may be at
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`increased risk. (5.3)
` Laboratory Monitoring –Recommended due to potential changes in
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`lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. (5.4)
`Immunizations – Live vaccines: Avoid use with XELJANZ. (5.5)
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`
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`------------------------------ADVERSE REACTIONS------------------------------­
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`The most commonly reported adverse reactions during the first 3 months in
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`controlled clinical trials (occurring in greater than or equal to 2% of patients
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`treated with XELJANZ monotherapy or in combination with DMARDs) were
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`upper respiratory tract infections, headache, diarrhea and nasopharyngitis.
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`(6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc at
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`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`---------------------------------DRUG INTERACTIONS---------------------------­
` Potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g.,
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`ketoconazole): Reduce dose to 5 mg once daily. (2.3, 7.1)
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` One or more concomitant medications that result in both moderate
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`inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g.,
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`fluconazole): Reduce dose to 5 mg once daily. (2.3, 7.2)
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` Potent CYP inducers (e.g., rifampin): May result in loss of or reduced
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`clinical response. (2.3, 7.3)
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`See 17 for PATIENT COUNSELING INFORMATION and
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`Medication Guide.
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`Revised: 12/2015
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.3 Nursing Mothers
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`8.6 Use in Diabetics
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`8.7 Hepatic Impairment
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`8.8 Renal Impairment
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the Full Prescribing Information
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`are not listed.
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`FULL PRESCRIBING INFORMATION
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` WARNING: SERIOUS INFECTIONS AND MALIGNANCY
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`•
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`SERIOUS INFECTIONS
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`Patients treated with XELJANZ are at increased risk for developing serious infections that
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`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
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`immunosuppressants such as methotrexate or corticosteroids.
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`If a serious infection develops, interrupt XELJANZ until the infection is controlled.
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`Reported infections include:
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`• Active tuberculosis, which may present with pulmonary or extrapulmonary disease.
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`Patients should be tested for latent tuberculosis before XELJANZ use and during
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`therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
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`Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with
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`invasive fungal infections may present with disseminated, rather than localized, disease.
`• Bacterial, viral, and other infections due to opportunistic pathogens.
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`The risks and benefits of treatment with XELJANZ should be carefully considered prior to
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`initiating therapy in patients with chronic or recurrent infection.
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`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
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`initiating therapy [see Warnings and Precautions (5.1)].
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`MALIGNANCIES
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`Lymphoma and other malignancies have been observed in patients treated with
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`XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder
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`has been observed at an increased rate in renal transplant patients treated with XELJANZ
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`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
`
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`immunosuppressants such as azathioprine and cyclosporine is not recommended.
`
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`Reference ID: 3864584
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`
`2
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`

`

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`2 DOSAGE AND ADMINISTRATION
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`2.1 Dosage in Rheumatoid Arthritis
` XELJANZ may be used as monotherapy or in combination with methotrexate or other
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`nonbiologic disease-modifying antirheumatic drugs (DMARDs). The recommended dose of
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`XELJANZ is 5 mg twice daily.
` XELJANZ is given orally with or without food.
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`2.2 Dosage Modifications due to Serious Infections and Cytopenias (see Tables 1, 2, and 3
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`below.)
`
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`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
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`or who have hemoglobin levels less than 9 g/dL.
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` Dose interruption is recommended for management of lymphopenia, neutropenia and anemia
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`[see Warnings and Precautions (5.4) and Adverse Reactions (6.1)] .
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` Avoid use of XELJANZ if a patient develops a serious infection until the infection is
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`controlled.
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`2.3 Dosage Modifications due to Drug Interactions
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` XELJANZ dosage should be reduced to 5 mg once daily in patients:
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`
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`receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole).
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`
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`receiving one or more concomitant medications that result in both moderate inhibition of
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`CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
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` Coadministration of potent inducers of CYP3A4 (e.g., rifampin) with XELJANZ may result
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`in loss of or reduced clinical response to XELJANZ. Coadministration of potent inducers of
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`CYP3A4 with XELJANZ is not recommended.
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`2.4 Dosage Modifications in Patients with Renal or Hepatic Impairment
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` XELJANZ dosage should be reduced to 5 mg once daily in patients:
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` with moderate or severe renal insufficiency.
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` with moderate hepatic impairment.
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` Use of XELJANZ in patients with severe hepatic impairment is not recommended.
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` Table 1: Dose Adjustments for Lymphopenia
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` Low Lymphocyte Count [see Warnings and Precautions (5.4)]
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` Recommendation
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` Lab Value
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` (cells/mm3)
` Lymphocyte count greater
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` than or equal to 500
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` Lymphocyte count less than
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` 500
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` (Confirmed by repeat testing)
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` Maintain dose
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` Discontinue XELJANZ
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`Reference ID: 3864584
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`3
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`

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` Lab Value
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` (cells/mm3)
` ANC greater than 1000
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` ANC 500-1000
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`Table 2: Dose Adjustments for Neutropenia
` Low ANC [see Warnings and Precautions (5.4)]
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` Recommendation
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` Maintain dose
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` For persistent decreases in this range, interrupt dosing until ANC is greater than
` 1000
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` When ANC is greater than 1000, resume XELJANZ 5 mg twice daily
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` Discontinue XELJANZ
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` ANC less than 500
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` (Confirmed by repeat testing)
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` Table 3: Dose Adjustments for Anemia
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` Low Hemoglobin Value [see Warnings and Precautions (5.4)]
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` Recommendation
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` Maintain dose
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` Interrupt the administration of XELJANZ until hemoglobin values have normalized
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` Lab Value
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` Less than or equal to 2 g/dL
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` decrease and greater than or
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` equal to 9.0 g/dL
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` Greater than 2 g/dL decrease
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` or less than 8.0 g/dL
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` (Confirmed by repeat testing)
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` 3 DOSAGE FORMS AND STRENGTHS
` XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White,
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` round, immediate-release film-coated tablets, debossed with “Pfizer” on one side, and “JKI 5” on
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` the other side.
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`4 CONTRAINDICATIONS
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`None
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`5 WARNINGS AND PRECAUTIONS
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`
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`5.1 Serious Infections
`Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or
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`other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving
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`XELJANZ. The most common serious infections reported with XELJANZ included pneumonia,
`cellulitis, herpes zoster, urinary tract infection, and diverticulitis [see Adverse Reactions (6.1)].
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`Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis,
`esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and
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`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
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`methotrexate or corticosteroids.
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`Other serious infections that were not reported in clinical studies may also occur
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`(e.g., histoplasmosis, coccidioidomycosis, and listeriosis).
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`
`Reference ID: 3864584
`
`
`4
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`

`

`
`
`
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` Avoid use of XELJANZ in patients with an active, serious infection, including localized
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`
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`
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` infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ
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` in patients:
`• with chronic or recurrent infection
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`• who have been exposed to tuberculosis
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`• with a history of a serious or an opportunistic infection
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`• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
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`• with underlying conditions that may predispose them to infection.
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`Patients should be closely monitored for the development of signs and symptoms of infection
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`during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient
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`develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new
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`infection during treatment with XELJANZ should undergo prompt and complete diagnostic
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`testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should
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`be initiated, and the patient should be closely monitored.
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`Tuberculosis
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`Patients should be evaluated and tested for latent or active infection prior to administration of
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`XELJANZ.
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`Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in
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`patients with a past history of latent or active tuberculosis in whom an adequate course of
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`treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but
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`who have risk factors for tuberculosis infection. Consultation with a physician with expertise in
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`the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti­
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`tuberculosis therapy is appropriate for an individual patient.
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`Patients should be closely monitored for the development of signs and symptoms of tuberculosis,
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`including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
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`
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`Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before
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`administering XELJANZ.
`
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`Viral Reactivation
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`Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were
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`observed in clinical studies with XELJANZ. The impact of XELJANZ on chronic viral hepatitis
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`reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from
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`clinical trials. Screening for viral hepatitis should be performed in accordance with clinical
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`guidelines before starting therapy with XELJANZ. The risk of herpes zoster is increased in
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`patients treated with XELJANZ and appears to be higher in patients treated with XELJANZ in
`Japan.
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`
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`5.2 Malignancy and Lymphoproliferative Disorders
`Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with
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`a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or
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`
`
`Reference ID: 3864584
`
`
`5
`
`

`

`
`
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`when considering continuing XELJANZ in patients who develop a malignancy. Malignancies
`were observed in clinical studies of XELJANZ [see Adverse Reactions (6.1)].
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`
`
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`
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`In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma
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`
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`were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to
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`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: 3864584
`
`
`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: 3864584
`
`
`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: 3864584
`
`
`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.
`
`
`
`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
`
`
`
`Reference ID: 3864584
`
`
`9
`
`

`

`
`
`
`
`
`
`
`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)].
`
`
`
`
`
`Reference ID: 3864584
`
`
`10
`
`

`

`
`
`
`
`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 m