CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s008
`
`
` Trade Name:
`
`Xeljanz
`
`
`
`
`Generic Name: Tofacitinib
`
`Pfizer, Inc.
`Sponsor:
`
`
`
`Approval Date: 02/11/2015
`
`
`Indication:
`
`
`
`Xeljanz is an inhibitor of Janus kinases (JAKs)
`indicated for the treatment of adult patients with
`moderately to severely active RA who have had an
`inadequate response or intolerance to methotrexate.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s008
`
`
`CONTENTS
`
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s008
`
`
`APPROVAL LETTER
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`REMOVE REMS ELEMENT
`REMS ASSESSMENT PLAN REVISION
`
`
`NDA 203214/S-008
`
`PF PRISM C.V.
`c/o Pfizer, Inc.
`445 Eastern Road
`Groton, CT 06340
`
`Attention: James T. Mayne, PhD, DABT
`Senior Director, Worldwide Safety and Regulatory
`
`
`Dear Dr. Mayne:
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received November
`
`
`7, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Xeljanz (tofacitinib) 5 mg tablets.
`
`
`We also refer to our REMS Modification Notification letter, dated September 9, 2014, in which
`we notified you that the Medication Guide should be removed as an element of the REMS to
`decrease the burden on the healthcare delivery system of complying with the REMS. We also
`
`notified you that the REMS assessment plan should be revised.
`
`This Prior Approval Supplemental New Drug Application proposes to eliminate the requirement
`
`
`for the approved Medication Guide as an element of the approved Xeljanz REMS.
`
`We have completed our review of this supplemental application. It is approved, effective on the
`
`date of this letter.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`The REMS for Xeljanz (tofacitinib) was originally approved on November 6, 2012, and REMS
`modifications were approved on November 8, 2013 and March 26, 2014. The REMS consists of
`a Medication Guide, communication plan, and timetable for submission of assessment of the
`REMS.
`
`Your proposed modification to the REMS consists of eliminating the requirement for the
`Medication Guide as an element of the REMS.
`
`We have determined that maintaining the Medication Guide as part of the approved labeling is
`adequate to address the serious and significant public health concern and meets the standard in
`
`Reference ID: 3700802
`
`
`

`

`
` NDA 203214/S-008
`
` Page 2
`
` 21 CFR 208.1. Therefore, it is no longer necessary to include the Medication Guide as an
`
` element of the approved REMS to ensure that the benefits of Xeljanz (tofacitinib) outweigh the
`
`risks.
`
` Therefore, we agree with your proposal, and a Medication Guide is no longer required as part of
`
`
` the REMS for Xeljanz (tofacitinib).
`
`Your proposed modified REMS submitted on November 7, 2014 and appended to this letter is
`approved.
`
`The modified REMS consists of a communication plan and a timetable for submission of
`assessments for the REMS.
`
`
`
` We remind you that the Medication Guide will continue to be part of the approved labeling for
`Xeljanz (tofacitinib) in accordance with 21 CFR 208.
`
`The timetable for submission of assessments of the REMS will remain the same as that approved
`on November 6, 2012.
`
`
`
`REMS ASSESSMENT PLAN
`
`Our March 26, 2014, Supplement Approval/REMS Modification Approval, letter described the
`REMS assessment plan. As described in our September 9, 2014, letter, the REMS assessment
`plan should be revised to remove the Survey of Patient Knowledge and Understanding since the
`REMS goals will be revised to only include healthcare providers.
`
`The revised REMS assessment plan should include, but is not limited to the following:
`
`i. A survey of physicians’ knowledge and understanding of the serious risks of tofacitinib
`
`will be made.
`
`ii. A survey of pharmacists’ knowledge and understanding of the serious risks of
`
`tofacitinib will be made.
`
`
`iii. An assessment and conclusions regarding the success of the REMS in meeting the
`stated goals will be made.
`
`iv. An assessment of the communication plan including:
`o The source(s) of the list of healthcare professionals to whom the Dear Healthcare Provider
`
`
`
`Letter, Dear Pharmacist Letter are distributed
`
`o
` Journal information pieces published, including date and journal name, volume, and issue
`
`
`o The date of launch of the communication plan (Dear Healthcare Provider Letter, Dear
`
`Pharmacist Letter, website, and journal information pieces)
`
`Reference ID: 3700802
`
`
`

`

`
` NDA 203214/S-008
`
` Page 3
`
`o The number of recipients of the Dear Healthcare Provider and Dear Pharmacist Letters
`o Date(s) of distribution of the Dear Healthcare Provider and Dear Pharmacist Letters
`
`o The number of returned and refused letters
`
`The requirements for assessments of an approved REMS under section 505-1(g)(3) include with
`respect to each goal included in the strategy, an assessment of the extent to which the approved
`strategy, including each element of the strategy, is meeting the goal or whether 1 or more such
`
`goals or such elements should be modified.
`
`In addition to the assessments submitted according to the timetable included in the approved
`REMS, you must submit a REMS assessment and may propose a modification to the approved
`REMS when you submit a supplemental application for a new indication for use as described in
`section 505-1(g)(2)(A) of FDCA.
`
`If the assessment instruments and methodology for your REMS assessments are not included in
`
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`
`
`
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`
`
`in bold capital letters at the top of the first page of the submission:
`
`NDA 203214 REMS CORRESPONDENCE
`
`(insert concise description of content in bold capital letters, e.g.,
`
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`
`METHODOLOGY)
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`
` Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`contact us to discuss what will be required in the authorized generic drug REMS submission.
`
` Prominently identify the submission containing the REMS assessments or proposed
`
`
`modifications of the REMS with the following wording in bold capital letters at the top of the
`first page of the submission as appropriate:
`
`NDA 203214 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 203214
`
`PROPOSED REMS MODIFICATION
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`Reference ID: 3700802
`
`
`

`

`
` NDA 203214/S-008
`
` Page 4
`
`FOR NDA 203214
`REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, 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(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`
`Because none of these criteria apply to your application, you are exempt from this requirement.
`
`REPORTING REQUIREMETNS
`
`
`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, call Carol F. Hill, Safety Regulatory Health Project Manager, at (301)
`
`
`
`796-1226.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Sally Seymour, MD
`
`Deputy Director for Safety
`
`Division of Pulmonary, Allergy, and Rheumatology
`
`Products
`Office of Drug Evaluation II
`
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`REMS
`
`Reference ID: 3700802
`
`
`

`

`REMS
`Initial REMS Approval: 11/06/2012
`Most Recent Modification: February/2015
`
`NDA 203,214 XELJANZ® (TOFACITINIB)
`
` PF PRISM C.V.
`
`c/o Pfizer Netherlands, Rivium Westlaan 142
`
`2909 LD Capelle aan den Ijssel
`
`
`NETHERLANDS
`
`
`Authorized U.S. Agent: Pfizer Inc, NY
`
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`
`GOAL
`
`The goal of the XELJANZ REMS is to inform healthcare providers about the serious risks
`
`associated with XELJANZ treatment.
`
`REMS ELEMENTS:
`
`Communication Plan
`
`Pfizer Inc will implement a communication plan to the following healthcare providers:
`
`x Rheumatologists and rheumatology healthcare providers (including physician assistants and
`nurse practitioners) who are likely to prescribe XELJANZ,
`
`
`x
`
`Infectious disease specialists who may be consulted about and treat serious infections
`including herpes zoster, tuberculosis, and other opportunistic infections,
`
`x Family practitioners, general practitioners, and internal medicine specialists who may be
`consulted about and be involved in treating serious infections, decreases in neutrophil counts,
`decrease in lymphocyte counts, decreases in hemoglobin, and lipid elevations and
`hyperlipidemia,
`
`x Emergency medicine specialists who may evaluate and treat serious infections including
`herpes zoster, and tuberculosis and other opportunistic infections in emergency care settings,
`
`
`and
`
`x Pharmacists who will dispense XELJANZ.
`
`1
`
`Reference ID: 3700802
`
`
`

`

`Elements of the communication plan include the following:
`
`1. A Dear Healthcare Provider Letter will be distributed twice annually for 3 years to
`rheumatologists and rheumatology healthcare providers (including physician assistants
`and nurse practitioners), infectious disease specialists, family practitioners, general
`practitioners, internal medicine specialists, and emergency medicine specialists through
`both traditional mailing and electronic mailing. The initial letter will be distributed
`within 60 days of product approval. The Dear Healthcare Provider letter is enclosed in
`
`Appendix A.
`
`The Prescribing Information and a copy of the Medication Guide will also be distributed
`
`
`in this communication.
`
`2. A Dear Pharmacist letter will be distributed to pharmacists twice annually for 3 years
`
`through both traditional mailing and electronic mailing. The initial letter will be
`
`
`distributed within 60 days of product approval. The Dear Pharmacist Letter is enclosed
`
`in Appendix B.
`
`3. Dissemination of information about the known and potential serious risks associated with
`XELJANZ will be made to healthcare providers through certain professional societies’
`
`
`scientific meetings and journals.
`o Display, for 2 years following product approval, as a panel/poster and distribution as
`printed material at major convention meetings of rheumatologists and other
`
`healthcare professionals specializing in rheumatology where the company has a
`
`
`
`
`sponsored booth (e.g., American College of Rheumatology, Congress of Clinical
`Rheumatology, and American Society of Health System Pharmacists annual
`meetings).
`o Quarterly, for 3 years following product approval, presentation as a printed
`
`information piece in The Rheumatologist, Arthritis & Rheumatology, Arthritis Care &
`
`
`
`
`Research, Clinical Infectious Diseases, Annals of Emergency Medicine, American
`Family Physician, Annals of Internal Medicine, American Journal of Health-System
`Pharmacy, and Journal of the Academy of Managed Care Pharmacy. The drafts of
`the important drug warning that will be printed in the aforementioned scientific
`
`
`journals are enclosed in Appendices C through Appendix G.
`
`4. Pfizer will ensure that all materials listed in or appended to the XELJANZ REMS
`
`program will be available through the XELJANZ REMS program website
`
`
`www.XELJANZREMS.com. The XELJANZ REMS program website will exist for
`3 years following approval of the REMS. The landing page for the XELJANZ REMS
`
`
`website is appended (see Appendix H).
`
`
`Timetable for Submission of Assessments
`
`
`
`Pfizer will submit REMS Assessments to the FDA at 18 months, by 3 years and 7 years from the
`
`
`date of approval of the REMS (11-06-2012). To facilitate inclusion of as much information as
`possible while allowing reasonable time to prepare the submission, the reporting interval covered
`
`
`Reference ID: 3700802
`
`
`2
`
`

`

`by each assessment should conclude no earlier than 60 days before the submission date for that
`assessment. Pfizer will submit each assessment so that it will be received by the FDA on or
`before the due date.
`
`Reference ID: 3700802
`
`
`3
`
`

`

`
`
` Appendix A: Dear HealthCare Provider Letter
`
`
`
`
`
`
`
`
` IMPORTANT DRUG WARNING
`
`
`
`Subject:
`
` Risk of serious infections, malignancies, decreases in peripheral lymphocyte
`
`
` counts, neutrophil counts, hemoglobin, and increases in lipid parameters in
`peripheral blood with XELJANZ““ (tofacitinib)
`
`Dear Healthcare Provider,
`
`The purpose of this letter is to inform you of important safety information for XELJANZ “
`
`
`
`(tofacitinib citrate), an inhibitor of Janus kinases (JAKs) approved by the Food and Drug
`
`
`Administration (FDA) for adult patients with moderately to severely active rheumatoid arthritis
`
`(RA) 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). The recommended dose of XELJANZ is 5 mg twice daily.
`
`The safety and efficacy of XELJANZ “ for conditions other than RA have not yet been
`
`
`established.
`
`FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) is necessary for
`
`
`XELJANZ to ensure that the benefits of the drug outweigh the potential risks.
`
`Limitations of Use
`
`XELJANZ is not recommended to be used in combination with biologic DMARDs or potent
`immunosuppressants such as azathioprine and cyclosporine.
`
`Patient Counseling
`
`You must discuss the risks associated with XELJANZ therapy with patients and in applicable
`instances with their caregivers.
`
`Serious Risks of XELJANZ“ (tofacitinib)
`
`Serious Infections
`
`
`x Patients treated with XELJANZ are at increased risk for developing serious infections
`leading to hospitalization or death, including active tuberculosis (TB), invasive fungal
`
`infections, bacterial, viral and other infections due to opportunistic pathogens. Most patients
`
`Reference ID: 3700802
`
`
`4
`
`

`

`who developed these infections were taking concomitant immunosuppressants such as
`
`methotrexate or corticosteroids.
`
`x Avoid use of XELJANZ in patients with an active infection, including localized infections.
`
`If a serious infection develops, XELJANZ should be interrupted until the infection is
`controlled.
`
`x Prior to initiating XELJANZ, a test for latent TB should be performed. If the test is positive,
`treatment for TB should be started prior to starting XELJANZ. All patients should be
`
`monitored for active TB during treatment, including patients who tested negative for latent
`
`
`TB prior to initiating therapy.
`
`
`
`x Cases of viral reactivation were observed in clinical studies with XELJANZ. Screening for
`
`viral hepatitis should be performed in accordance with clinical guidelines before starting
`
`therapy with XELJANZ.
`
`
`Malignancies and Lymphoproliferative Disorders
`
`x Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients
`with a known malignancy other than a successfully treated non-melanoma skin cancer
`
`
`(NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.
`
`Lymphoma and other malignancies have been reported in patients treated with XELJANZ.
`
`x
`
`x
`
`In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one
`
`lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD,
`compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without
`DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have
`also been observed in the long-term extension studies in rheumatoid arthritis patients treated
`with XELJANZ.
`
`In Phase 2B, controlled dose-ranging studies 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.
`
`x Non-melanoma skin cancers have been reported in patients treated with XELJANZ and
`identified as an adverse drug reaction. Periodic skin examination is recommended for
`
`patients who are at increased risk for skin cancer.
`
`Important Information on Laboratory Abnormalities
`
`x Lymphocytes, neutrophils, hemoglobin, and lipids should be monitored, as abnormalities in
`these parameters were associated with XELJANZ treatment in Phase 3 clinical trials.
`
`
`Reference ID: 3700802
`
`
`5
`
`

`

`Medication Guide
`The Medication Guide contains information that can be used to facilitate discussions about the
`known and potential risks of therapy. A copy is enclosed. The XELJANZ Medication Guide
`must be provided to patients being treated with XELJANZ or to their caregiver at the time of
`
`
`first dose or if the Medication Guide is materially changed. Additional copies of the Medication
`
`Guide may be obtained from the XELJANZ REMS web site (www.XELJANZREMS.com) or by
`
`
`calling Pfizer at 1-800-438-1985.
`
`Reporting Adverse Events
`To report any adverse events with the use of XELJANZ, contact:
`
`x Pfizer Safety at 1-800-438-1985
`x MedWatch (FDA safety information and adverse event reporting program) at 1-800-332-
`1088 or online at www.fda.gov/medwatch/report.htm
`
`This letter is not a comprehensive description of the risks associated with the use of XELJANZ.
`Please read the accompanying Prescribing Information, including BOXED WARNING, and
`
`
`Medication Guide for a complete description of these risks.
`
`For more information, please call Pfizer Medical Information at 1-800-438-1985 or visit the
`XELJANZ REMS web site (www.XELJANZREMS.com).
`
`Sincerely,
`
`Chief Medical Officer
`Pfizer
`
`Enclosure
`
`Reference ID: 3700802
`
`
`6
`
`

`

`
`
` Appendix B: Dear Pharmacist Letter
`
`
`
` IMPORTANT DRUG WARNING
`
`
`
`Dear Pharmacist,
`
`The purpose of this letter is to inform you of important safety information for XELJANZ “
`
`
`
`(tofacitinib citrate), an inhibitor of Janus kinases (JAKs) approved by the Food and Drug
`
`
`Administration (FDA) for adult patients with moderately to severely active rheumatoid arthritis
`(RA) 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). The recommended dose of XELJANZ is 5 mg twice daily.
`
`The safety and efficacy of XELJANZ “ for conditions other than RA have not yet been
`
`
`established.
`
`
`FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) is necessary for
`XELJANZ to ensure that the benefits of the drug outweigh the potential risks.
`
`Limitations of Use
`
`XELJANZ is not recommended to be used in combination with biologic DMARDs or potent
`immunosuppressants such as azathioprine and cyclosporine.
`
`Serious Risks of XELJANZ““ (tofacitinib)
`
`Serious Infections
`
`x Patients treated with XELJANZ are at increased risk for developing serious infections
`leading to hospitalization or death, including active tuberculosis (TB), invasive fungal
`
`infections, bacterial, viral and other infections due to opportunistic pathogens. Most patients
`
`who developed these infections were taking concomitant immunosuppressants such as
`methotrexate or corticosteroids.
`
`
`x Avoid use of XELJANZ in patients with an active infection, including localized infections.
`If a serious infection develops, XELJANZ should be interrupted until the infection is
`controlled.
`
`x Prior to initiating XELJANZ, a test for latent TB should be performed. If the test is positive,
`
`treatment for TB should be started prior to starting XELJANZ. All patients should be
`
`Reference ID: 3700802
`
`
`7
`
`

`

`monitored for active TB during treatment, including patients who tested negative for latent
`
`
`TB prior to initiating therapy.
`
`
`
`x Cases of viral reactivation were observed in clinical studies with XELJANZ. Screening for
`
`viral hepatitis should be performed in accordance with clinical guidelines before starting
`
`therapy with XELJANZ.
`
`
`Malignancies and Lymphoproliferative Disorders
`
`x Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients
`with a known malignancy other than a successfully treated non-melanoma skin cancer
`
`
`(NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.
`
`Lymphoma and other malignancies have been reported in patients treated with XELJANZ.
`
`x
`
`x
`
`In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one
`
`lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD,
`compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without
`DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have
`also been observed in the long-term extension studies in rheumatoid arthritis patients treated
`with XELJANZ.
`
`In Phase 2B, controlled dose-ranging studies 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.
`
`x Non-melanoma skin cancers have been reported in patients treated with XELJANZ and
`identified as an adverse drug reaction. Periodic skin examination is recommended for
`
`patients who are at increased risk for skin cancer.
`
`Important Information on Laboratory Abnormalities
`
`x Lymphocytes, neutrophils, hemoglobin, and lipids should be monitored, as abnormalities in
`these parameters were associated with XELJANZ treatment in Phase 3 clinical trials.
`
`
`Medication Guide
`The FDA requires that a copy of the enclosed XELJANZ Medication Guide be distributed to
`
`patients who receive XELJANZ or to their caregiver at the time of dispensing or if the
`Medication Guide is materially changed. Additional copies of the Medication Guide may be
`
`obtained from the XELJANZ REMS web site (www.XELJANZREMS.com) or by calling Pfizer
`
`
`
`
`at 1-800-438-1985.
`
`Reporting Adverse Events
`To report any adverse events with the use of XELJANZ, contact:
`
`x Pfizer Safety at 1-800-438-1985
`
`Reference ID: 3700802
`
`
`8
`
`

`

` x MedWatch (FDA safety information and adverse event reporting program) at 1-800-332-
`
`1088 or online at www.fda.gov/medwatch/report.htm
`
`This letter is not a comprehensive description of the risks associated with the use of XELJANZ.
`Please read the accompanying Prescribing Information, including BOXED WARNING, and
`
`
`Medication Guide for a complete description of these risks.
`
`For more information, please call Pfizer Medical Information at 1-800-438-1985 or visit the
`XELJANZ REMS web site (www.XELJANZREMS.com).
`
`
`Sincerely,
`
`Chief Medical Officer
`Pfizer
`
`Enclosure
`
`Reference ID: 3700802
`
`
`9
`
`

`

`Appendix C: Journal Information Piece For Rheumatologists or Rheumatology Healthcare
`Providers (including physician assistants and nurse practitioners)
`
`Important Drug Warning for Rheumatologists and Rheumatology Healthcare Providers
`(including physician assistants and nurse practitioners) about Risks and Potential Risks
`
`with XELJANZ
`
`XELJANZ “ (tofacitinib citrate) is an inhibitor of Janus kinases (JAKs) approved by the Food
`
`
`
`
`
`and Drug Administration (FDA) for adult patients with moderately to severely active rheumatoid
`
`arthritis (RA) 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). The recommended dose of XELJANZ is 5 mg
`twice daily.
`
`The safety and efficacy of XELJANZ “ for conditions other than RA have not yet been
`
`
`established.
`
`Limitations of Use
`
`XELJANZ is not recommended to be used in combination with biologic DMARDs or potent
`immunosuppressants such as azathioprine and cyclosporine.
`
`Serious Risks of XELJANZ““ (tofacitinib)
`Serious Infections: Patients treated with XELJANZ are at increased risk for developing serious
`
`infections leading to hospitalization or death, including active tuberculosis (TB), invasive fungal
`
`infections, bacterial, viral and other infections due to opportunistic pathogens. Avoid use of
`XELJANZ in patients with an active infection, including localized infections. If a serious
`infection develops, XELJANZ should be interrupted until the infection is controlled.
`
`Malignancies and Lymphoproliferative Disorders: Consider the risks and benefits of
`
`
`
`
`
`XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a
`
`
`successfully treated non-melanoma skin cancer (NMSC) or when considering continuing
`XELJANZ in patients who develop a malignancy. Lymphoma, solid cancers, and NMSC have
`
`been reported in patients treated with XELJANZ. NMSC has been identified as an adverse drug
`reaction.
`
`
`Laboratory Abnormalities: Lymphocytes, neutrophils, hemoglobin, and lipids should be
`monitored, as abnormalities in these parameters were associated with XELJANZ treatment in
`
`
`Phase 3 clinical trials. Please see the full Prescribing Information for more information.
`
`Reporting Adverse Events
`
`To report any adverse events with the use of XELJANZ, contact:
`x Pfizer Safety at 1-800-438-1985
`x MedWatch (FDA safety information and adverse event reporting program) at 1-800-332-
`1088 or online at www.fda.gov/medwatch/report.htm
`
`Reference ID: 3700802
`
`
`10
`
`

`

` This is not a comprehensive representation of the potential risks associated with use of
`
`
`
` XELJANZ. For a complete description of these potential risks, please visit the XELJANZ
` REMS web site (www.XELJANZREMS.com) for Prescribing Information and Medication
`
`Guide.
`
`Reference ID: 3700802
`
`
`11
`
`
`

`

`Appendix D: Journal Information Piece For Infectious Disease Specialists
`
`
`Important Drug Warning for Infectious Disease Specialists about Risks and Potential Risks
`with XELJANZ
`
` XELJANZ “ (tofacitinib citrate) is an inhibitor of Janus kinases (JAKs) approved by the Food
`
`
`
`
` and Drug Administration (FDA) for adult patients with moderately to severely active rheumatoid
` arthritis (RA) 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). The recommended dose of XELJANZ is 5 mg
`
`
`twice daily.
`
`
`
`The safety and efficacy of XELJANZ “ for conditions other than RA have not yet been
`
`
`established.
`
`Limitations of Use
`
`XELJANZ is not recommended to be used in combination with biologic DMARDs or potent
`immunosuppressants such as azathioprine and cyclosporine.
`
`Serious Risks of XELJANZ““ (tofacitinib)
`Serious Infections: Patients treated with XELJANZ are at increased risk for developing serious
`
`infections leading to hospitalization or death, including active tuberculosis (TB), invasive fungal
`
`infections, bacterial, viral and other infections due to opportunistic pathogens. Avoid use of
`XELJANZ in patients with an active infection, including localized infections. If a serious
`infection develops, XELJANZ should be interrupted until the infection is controlled.
`
`Malignancies and Lymphoproliferative Disorders: Consider the risks and benefits of
`
`
`
`
`
`XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a
`
`
`successfully treated non-melanoma skin cancer (NMSC) or when considering continuing
`XELJANZ in patients who develop a malignancy. Lymphoma, solid cancers, and NMSC have
`
`been reported in patients treated with XELJANZ. NMSC has been identified as an adverse drug
`reaction.
`
`
`Laboratory Abnormalities: Lymphocytes, neutrophils, hemoglobin, and lipids should be
`monitored, as abnormalities in these parameters were associated with XELJANZ treatment in
`
`
`Phase 3 clinical trials. Please see the full Prescribing Information for more information.
`
`Reporting Adverse Events
`
`To report any adverse events with the use of XELJANZ, contact:
`x Pfizer Safety at 1-800-438-1985
`x MedWatch (FDA safety information and adverse event reporting program) at 1-800-332-
`1088 or online at www.fda.gov/medwatch/report.htm
`
`This is not a comprehensive representation of the potential risks associated with use of
`
`XELJANZ. For a complete description of these potential risks, please visit the XELJANZ
`
`
`
`Reference ID: 3700802
`
`
`12
`
`

`

`
`
` REMS web site (www.XELJANZREMS.com) for Prescribing Information and Medication
`Guide.
`
`Reference ID: 3700802
`
`
`13
`
`
`

`

`
`
` Appendix E: Journal Information Piece For Family Practitioners, General Practitioners,
`
` and Internal Medicine Specialists
`
`
`
`Important Drug Warning for Family Practitioners, General Practitioners, and Internal
`Medicine Specialists about Risks and Potential Risks with XELJANZ
`
`
`
`XELJANZ “ (tofacitinib citrate) is an inhibitor of Janus kinases (JAKs) approved by the Food
`
`
`
`
`
`and Drug Administration (FDA) for adult patients with moderately to severely active rheumatoid
`
`arthritis (RA) 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). The recommended dose of XELJANZ is 5 mg
`twice daily.
`
`The safety and efficacy of XELJANZ “ for conditions other than RA have not yet been
`
`
`established.
`
`Limitations of Use
`
`XELJANZ is not recommended to be used in combination with biologic DMARDs or potent
`immunosuppressants such as azathioprine and cyclosporine.
`
`Serious Risks of XELJANZ““ (tofacitinib)
`Serious Infections: Patients treated with XELJANZ are at increased risk for developing serious
`
`infections leading to hospitalization or death, including active tuberculosis (TB), invasive fungal
`
`infections, bacterial, viral and other infections due to opportunistic pathogens. Avoid use of
`XELJANZ in patients with an active infection, including localized infections. If a serious
`infection develops, XELJANZ should be interrupted until the infection is controlled.
`
`Malignancies and Lymphoproliferative Disorders: Consider the risks and benefits of
`
`
`
`
`
`XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a
`
`
`successfully treated non-melanoma skin cancer (NMSC) or when considering continuing
`XELJANZ in patients who develop a malignancy. Lymphoma, solid cancers, and NMSC have
`
`been reported in patients treated with XELJANZ. NMSC has bee