CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`203214Orig1s018
`
`
`
`
`
` XELJANZ
`Trade Name:
`tofacitinib
`Generic or Proper
`Name:
`
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`
`PF Prism C.V. c/o Pfizer, Inc.
`May 30, 2018
`XELJANZ/XELJANZ XR is a Janus kinase (JAK)
`inhibitor.
` Rheumatoid Arthritis: XELJANZ/XELJANZ XR 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).
` Psoriatic Arthritis: XELJANZ/XELJANZ XR is
`indicated for the treatment of adult patients with active
`psoriatic arthritis who have had an inadequate response
`or intolerance to methotrexate or other disease-
`modifying antirheumatic drugs (DMARDs).
` Ulcerative Colitis: XELJANZ is indicated for the
`treatment of adult patients with moderately to severely
`active ulcerative colitis (UC).
`
`

`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`203214Orig1s018
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Officer/Employee List
`Multidiscipline Review(s)
` Summary Review
` Office Director
` Cross Discipline Team Leader
` Clinical
` Non-Clinical
` Statistical
` Clinical Pharmacology
`Product Quality Review(s)
`Clinical Microbiology / Virology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`
`X
`
`
`
`X
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203214Orig1s018
`
`
`APPROVAL LETTER
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 203214/S-018
`
`PF PRISM C.V.
`C/o Pfizer, Inc.
`Attention: Louis M. Ferrara
`Director, Worldwide Regulatory Strategy
`445 Eastern Point Road
`Groton, CT 06340
`
`Dear Mr. Ferrara:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`Please refer to your supplemental New Drug Application (sNDA) dated May 4, 2017, received
`May 4, 2017, and your amendments, submitted under section 505(b) of the Federal Food, Drug,
`and Cosmetic Act (FDCA), for XELJANZ (tofacitinib), 5 mg and 10 mg tablets.
`
`We acknowledge receipt of your major amendment dated September 28, 2017, which extended
`the goal date by three months.
`
`This Prior Approval supplemental new drug application provides for the treatment of adult
`patients with moderately to severely active ulcerative colitis (UC).
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of prescribing information.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, Medication
`
`Reference ID: 4269956
`
`

`

`NDA 203214/S-018
`Page 2
`
`Guide), with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`We acknowledge your May 10, 2018, submission containing final printed carton and container
`labels.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients (which includes new salts and new fixed combinations), new indications, new
`dosage forms, new dosing regimens, or new routes of administration are required to contain an
`assessment of the safety and effectiveness of the product for the claimed indication in pediatric
`patients unless this requirement is waived, deferred, or inapplicable.
`
`We are waiving the pediatric studies requirement for ages less than 2 years because necessary
`studies are impossible or highly impracticable. This is because there is a low incidence of the
`disease in this age group. In addition, difficulties exist in differentiating the subtypes of
`inflammatory bowel disease in infants and very young children.
`
`We are deferring submission of your pediatric studies for ages 2 to 17 years for this application
`because this product is ready for approval for use in adults and the pediatric studies have not
`been completed.
`
`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act are required postmarketing studies. The status of these postmarketing studies must
`be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(C) of the Federal Food,
`Drug, and Cosmetic Act. These required studies are listed below.
`
`Reference ID: 4269956
`
`

`

`NDA 203214/S-018
`Page 3
`
`3400-1 A one-year, multi-center, randomized, controlled trial to evaluate the safety,
`efficacy and pharmacokinetics of XELJANZ (tofacitinib) in pediatric patients 2 to
`17 years of age with moderately to severely active ulcerative colitis.
`
`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
`
`Draft Protocol Submission: 01/2018
`Final Protocol Submission: 10/2018
`Study/Trial Completion:
`04/2022
`Final Report Submission:
`09/2022
`
`3400-2 A multi-center open(cid:486)label extension study to evaluate the long-term safety of
`
`
`
`
`
`
`
`XELJANZ (tofacitinib) in pediatric patients 2 to 17 years of age with moderately
`to severely active ulcerative colitis who participated in PMR 3400-1.
`
`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
`
`Draft Protocol Submission: 01/2018
`Final Protocol Submission: 10/2018
`Study/Trial Completion:
`03/2024
`Final Report Submission:
`08/2024
`
`Submit the protocol(s) to your IND 111294, with a cross-reference letter to this NDA.
`
`Reports of these required pediatric postmarketing studies must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
`require holders of approved drug and biological product applications to conduct postmarketing
`studies and clinical trials for certain purposes, if FDA makes certain findings required by the
`statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess the signal of a serious
`
`Reference ID: 4269956
`
`

`

`NDA 203214/S-018
`Page 4
`
`risk of malignancies associated with the long-term use of XELJANZ (tofacitinib) in the
`treatment of adults with moderate to severe ulcerative colitis.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk. Therefore, based on
`appropriate scientific data, you are required to conduct the following:
`
`3400-3 A long(cid:486)term, observational study to assess the long(cid:486)term safety of tofacitinib 5mg
`
`BID or 10mg BID versus other therapies used in the treatment of adults with
`moderately to severely active ulcerative colitis. The study’s primary outcome is
`malignancy. Secondary outcomes of interest include, but are not limited to,
`opportunistic infections, thromboembolic events, and hepatic injury. Specify
`concise case definitions, and provide outcome validation for both primary and
`secondary outcomes. Describe and justify choice of appropriate comparator
`population(s) and estimated background rates relative to tofacitinib-exposed
`patients; clearly define the primary comparator population for the primary
`objective. Design the study around a testable hypothesis to assess, with sufficient
`sample size and power, a clinically meaningful increase in malignancy risk above
`
`the comparator background rate, with a pre(cid:486)specified statistical analysis method.
`
`For the tofacitinib-exposed and comparator(s), the study drug initiation period
`should be clearly defined, including any exclusion and inclusion criteria. Ensure
`adequate number of patients with at least 18 months of tofacitinib exposure at the
`end of the study. Follow for period of at least 7 years.
`
`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
`
`
`
`
`
`Draft Protocol Submission: 09/2018
`Final Protocol Submission: 01/2019
`Study Completion:
`
`01/2026
`Interim Report:
`
`01/2023
`Final Report Submission:
`06/2026
`
`Submit the protocol(s) to your IND 111294, with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final
`report(s) to your NDA. Prominently identify the submission with the following wording in bold
`capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`Submission of the protocol(s) for required postmarketing observational studies to your IND is for
`purposes of administrative tracking only. These studies do not constitute clinical investigations
`pursuant to 21 CFR 312.3(b) and therefore are not subject to the IND requirements under 21
`CFR part 312 or FDA’s regulations under 21 CFR parts 50 (Protection of Human Subjects) and
`56 (Institutional Review Boards).
`
`Reference ID: 4269956
`
`

`

`NDA 203214/S-018
`Page 5
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and
`21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and
`21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must
`also include a report on the status of any study or clinical trial otherwise undertaken to
`investigate a safety issue. Failure to submit an annual report for studies or clinical trials required
`under 505(o) on the date required will be considered a violation of FDCA section
`505(o)(3)(E)(ii) and could result in enforcement action.
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`A double(cid:486)blind, randomized, controlled clinical trial to assess the relative efficacy
`
`3400-4
`
`of XELJANZ (tofacitinib) 5mg BID versus 10mg BID for maintaining remission
`in patients with moderate to severe ulcerative colitis who are in stable remission
`for at least 6 months on XELJANZ (tofacitinib) 10mg BID therapy.
`
`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
`
`Draft Protocol Submission: 09/2018
`Final Protocol Submission: 12/2018
`Study/Trial Completion:
`01/2024
`Final Report Submission:
`07/2024
`
`3400-5
`
`A controlled clinical trial to assess both the clinical and immunological responses
`to Shingrix vaccination in adult patients with moderately to severely active
`ulcerative colitis treated with XELJANZ (tofacitinib).
`
`Reference ID: 4269956
`
`

`

`NDA 203214/S-018
`Page 6
`
`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
`
`Draft Protocol Submission: 10/2018
`Final Protocol Submission: 03/2019
`Study/Trial Completion:
`05/2022
`Final Report Submission:
`11/2022
`
`Submit clinical protocols to your IND 111294 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
`status summary of each commitment in your annual report to this NDA. The status summary
`should include expected summary completion and final report submission dates, any changes in
`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`Reference ID: 4269956
`
`

`

`NDA 203214/S-018
`Page 7
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, contact Kelly Richards, Senior Regulatory Health Project Manager, at
`(240) 402-4276.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Jessica J. Lee, MD, M.M.Sc.
`Associate Director
`Division of Gastroenterology and Inborn Errors Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 4269956
`
`

`

`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`JESSICA J LEE
`05/30/2018
`
`Reference ID: 4269956
`
`

`

`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203214Orig1s018
`
`
`LABELING
`
`

`

`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.
`
`(cid:120) 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)
`(cid:120) If a serious infection develops, interrupt XELJANZ/XELJANZ XR
`until the infection is controlled. (5.1)
`(cid:120) 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)
`(cid:120) Monitor all patients for active tuberculosis during treatment, even if
`the initial latent tuberculosis test is negative. (5.1)
`(cid:120) Lymphoma and other malignancies have been observed in patients
`treated with XELJANZ. Epstein Barr Virus-associated
`post-transplant lymphoproliferative disorder has been observed at an
`increased rate in renal transplant patients treated with XELJANZ
`and concomitant immunosuppressive medications. (5.2)
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`Indications and Usage (1)
`05/2018
`Dosage and Administration (2)
`05/2018
`Warnings and Precautions (5.1)
`05/2018
`Warnings and Precautions (5.2, 5.3)
`12/2017
`Warnings and Precautions (5.5)
`08/2017
`
` --------------------------- INDICATIONS AND USAGE----------------------------
`XELJANZ/XELJANZ XR is a Janus kinase (JAK) inhibitor.
`(cid:120) Rheumatoid Arthritis: XELJANZ/XELJANZ XR 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).
`(cid:380) 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)
`(cid:120) Psoriatic Arthritis: XELJANZ/XELJANZ XR is indicated for the
`treatment of adult patients with active psoriatic arthritis who have had an
`inadequate response or intolerance to methotrexate or other
`disease-modifying antirheumatic drugs (DMARDs).
`(cid:380) 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)
`(cid:120) Ulcerative Colitis: XELJANZ is indicated for the treatment of adult
`patients with moderately to severely active ulcerative colitis (UC).
`(cid:380) Limitations of Use Use of XELJANZ in combination with biological
`therapies for UC or with potent immunosuppressants such as
`azathioprine and cyclosporine is not recommended. (1)
`
` -----------------------DOSAGE AND ADMINISTRATION -----------------------
`Administration Instructions
`(cid:120) Do not initiate XELJANZ/XELJANZ XR if absolute lymphocyte count
`<500 cells/mm3, an absolute neutrophil count (ANC) <1000 cells/mm3 or
`hemoglobin <9 g/dL. (2.1)
`Recommended Dosage
`Rheumatoid Arthritis
`(cid:120) XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. (2.2)
`(cid:120) Recommended dosage in patients with moderate and severe renal
`impairment or moderate hepatic impairment is XELJANZ 5 mg once
`daily. (2, 8.7, 8.8)
`
`Psoriatic Arthritis (in combination with nonbiologic DMARDs)
`(cid:120) XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. (2.2)
`(cid:120) Recommended dosage in patients with moderate and severe renal
`impairment or moderate hepatic impairment is XELJANZ 5 mg once
`daily. (2, 8.7, 8.8)
`Ulcerative Colitis
`(cid:120) XELJANZ 10 mg twice daily for at least 8 weeks; then 5 or 10 mg
`twice daily. Discontinue after 16 weeks of 10 mg twice daily, if adequate
`therapeutic benefit is not achieved. Use the lowest effective dose to
`maintain response. (2.3)
`(cid:120) Recommended dosage in patients with moderate and severe renal
`impairment or moderate hepatic impairment: half the total daily dosage
`recommended for patients with normal renal and hepatic function. (2, 8.7,
`8.8)
`Dosage Adjustment
`(cid:120) See the full prescribing information for dosage adjustments by indication
`for patients receiving CYP2C19 and/or CYP3A4 inhibitors; in patients
`with moderate or severe renal impairment or moderate hepatic
`impairment; and patients with lymphopenia, neutropenia, or anemia. (2.2,
`2.3)
`(cid:120) Use of XELJANZ/XELJANZ XR in patients with severe hepatic
`impairment is not recommended in any patient population. (2.2, 2.3, 8.8)
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`XELJANZ Tablets: 5 mg, 10 mg tofacitinib (3)
`XELJANZ XR Tablets: 11 mg tofacitinib (3)
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`None (4)
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`(cid:120) Serious Infections: Avoid use of XELJANZ/XELJANZ XR during an
`active serious infection, including localized infections. (5.1)
`(cid:120) Gastrointestinal Perforations: Use with caution in patients that may be at
`increased risk. (5.3)
`(cid:120) 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)
`
`(cid:120)
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`Most common adverse reactions are:
`(cid:120) Rheumatoid and Psoriatic Arthritis: Reported during the first 3 months in
`rheumatoid arthritis controlled clinical trials and occurring in (cid:149)2% of
`patients treated with XELJANZ monotherapy or in combination with
`DMARDs: upper respiratory tract infection, nasopharyngitis, diarrhea,
`and headache. (6.1)
`(cid:120) Ulcerative Colitis: Reported in (cid:149)5% of patients treated with either 5 mg or
`10 mg twice daily of XELJANZ and (cid:149)1% greater than reported in patients
`receiving placebo in either the induction or maintenance clinical trials:
`nasopharyngitis, elevated cholesterol levels, headache, upper respiratory
`tract infection, increased blood creatine phosphokinase, rash, diarrhea,
`and herpes zoster. (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-------------------------------
`See full prescribing information for clinically relevant drug interactions. (2, 7)
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`Lactation: Advise not to breastfeed. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 05/2018
`
`Reference ID: 4269956
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1
`Important Administration Instructions
`2.2 Recommended Dosage in Rheumatoid Arthritis and Psoriatic
`Arthritis
`2.3 Recommended Dosage in Ulcerative Colitis
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
` Serious Infections
`5.1
`5.2 Malignancy and Lymphoproliferative Disorders
` Gastrointestinal Perforations
`5.3
` Laboratory Abnormalities
`5.4
` Vaccinations
`5.5
`5.6 Risk of Gastrointestinal Obstruction with a Non-Deformable
`Extended-Release Formulation such as XELJANZ XR
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
` Lactation
`8.2
`
`8.3 Females and Males of Reproductive Potential
` Pediatric Use
`8.4
` Geriatric Use
`8.5
`8.6 Use in Diabetics
` Renal Impairment
`8.7
` Hepatic Impairment
`8.8
`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
`14.1 Rheumatoid Arthritis
` Psoriatic Arthritis
`14.2
` Ulcerative Colitis
`14.3
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the Full Prescribing Information
`are not listed.
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`Reference ID: 4269956
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`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), 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, including herpes zoster, 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
`
`Rheumatoid Arthritis
`XELJANZ/XELJANZ XR 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: 4269956
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`(cid:120) 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.
`
`Psoriatic Arthritis
`XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic
`arthritis who have had an inadequate response or intolerance to methotrexate or other
`disease-modifying antirheumatic drugs (DMARDs).
`(cid:120) 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.
`
`Ulcerative Colitis
`XELJANZ is indicated for the treatment of adult patients with moderately to severely active
`ulcerative colitis (UC).
`(cid:120) Limitations of Use: Use of XELJANZ in combination with biological therapies for UC or
`with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Administration Instructions
`(cid:120) Do not initiate XELJANZ/XELJANZ XR 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.
`(cid:120) Dose interruption is recommended for management of lymphopenia, neutropenia, and
`anemia [see Warnings and Precautions (5.4), Adverse Reactions (6.1)].
`Interrupt use of XELJANZ/XELJANZ XR if a patient develops a serious infection until
`the infection is controlled [see Warnings and Precautions (5.1)].
`(cid:120) Take XELJANZ/XELJANZ XR with or without food [see Clinical Pharmacology
`(12.3)].
`(cid:120) Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.
`
`(cid:120)
`
`2.2 Recommended Dosage in Rheumatoid Arthritis and Psoriatic Arthritis
`Table 1 displays the recommended adult daily dosage of XELJANZ and XELJANZ XR and
`dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, in patients with
`moderate or severe renal impairment or moderate hepatic impairment, with lymphopenia,
`neutropenia, or anemia.
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`Table 1: Recommended Dosage of XELJANZ and XELJANZ XR in Patients with
`Rheumatoid Arthritis1 and Psoriatic Arthritis2
`XELJANZ
`5 mg twice daily
`
`XELJANZ XR
`11 mg once daily
`
`5 mg once daily
`
`Switch to
`XELJANZ 5 mg once daily
`
`5 mg once daily
`
`Switch to
`XELJANZ 5 mg once daily
`
`Discontinue dosing.
`
`Interrupt dosing.
`When ANC is greater than 1000,
`resume 5 mg twice daily.
`
`Interrupt dosing.
`When ANC is greater than 1000,
`resume 11 mg once daily.
`
`(cid:120)
`
`
`Adult patients
`Patients receiving:
`(cid:120) Strong CYP3A4 inhibitors
`(e.g., ketoconazole), or
`a moderate CYP3A4
`inhibitor(s) with a strong
`CYP2C19 inhibitor(s)
`(e.g., fluconazole)
`[see Drug Interactions (7)]
`Patients with:
`(cid:120) moderate or severe renal
`impairment [see Use in Specific
`Populations (8.7)]
`(cid:120) moderate hepatic impairment
`[see Use in Specific Populations
`(8.8)]*
`Patients with lymphocyte count less
`than 500 cells/mm3, confirmed by
`repeat testing
`Patients with ANC 500 to
`1000 cells/mm3
`
`Discontinue dosing.
`
`Patients with ANC less than
`500 cells/mm3
`Patients with hemoglobin less than
`8 g/dL or a decrease of more than
`2 g/dL
`1
`XELJANZ/XELJANZ XR may be used as monotherapy or in combination with methotrexate or other nonbiologic
`disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis.
`2 XELJANZ/XELJANZ XR is used in combination with nonbiologic disease modifying antirheumatic drugs
`(DMARDs) in psoriatic arthritis. The efficacy of XELJANZ/XELJANZ XR as a monotherapy has not been
`studied in psoriatic arthritis.
`* Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.
`
`Interrupt dosing until hemoglobin values have normalized.
`
`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.
`
`2.3 Recommended Dosage in Ulcerative Co