CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`
`
`
`
`Date:
`
`To:
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`FINAL REMS REVIEW
`
`
`
`
`
`
`November 6, 2012
`
`
`Reviewer(s)
`
`
`
`
`
`Badrul Chowdhury, M.D., Ph.D., Director,
`Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)
`
`Kendra Worthy, Pharm.D., Team Leader, Division of Risk Management
`(DRISK)
`Anahita Tavakoli, M.A., Health Communication Analyst, DRISK
`
`Claudia Manzo, Pharm. D., DRISK
`
`
`Review of Risk Evaluation and Mitigation Strategy (REMS)
`
`
`
`Division Director:
`
`
`
`Subject:
`
`
`Drug Name Xeljanz (Tofacitinib) 5 mg Tablet
`
`Indication: Treatment of adult patients with moderately to severely active
`rheumatoid arthritis who have had an inadequate response or intolerance
`to methotrexate.
`
`
`
`
`Therapeutic Class: Kinase Inhibitor (Janus Kinases JAKs family)
`
`Application Type /
`Number: NDA 20-3214
`
`Applicant: Pfizer
`
`OSE RCM #: 2012-1430
`
`
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`1
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`Reference ID: 3213370
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`

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`
`CONTENTS
`
`1 
`
`INTRODUCTION ................................................................................................................... 3 
`1.1. 
`BACKGROUND ............................................................................................................ 3 
`2.1  Brief Efficacy Overview ......................................................................................................... 3 
`2.2  Safety Overview ...................................................................................................................... 4 
`3  MATERIAL REVIEWED ...................................................................................................... 5 
`4 
`RESULTS OF REVIEW OF PROPOSED REMS .................................................................. 5 
`4.1  Need for a REMS .................................................................................................................... 5 
`4.2  Relevant REMS Background .................................................................................................. 6 
`4.3  Summary of November 5, 2012 Proposed REMS Amendment .............................................. 7 
`4.3.1 REMS Goals ............................................................................................................................ 7 
`4.3.2 REMS Elements ...................................................................................................................... 7 
`4.3.2.1  Medication Guide ............................................................................................................. 7 
`4.3.2.2  Communication Plan ........................................................................................................ 7 
`4.3.2.3  Timetable for Submission of Assessments ...................................................................... 8 
`4.3.3 REMS Assessment Plan .......................................................................................................... 9 
`5 
`DISCUSSION AND CONCLUSION: .................................................................................... 9 
`ATTACHMENT 1: Xeljanz REMS document .............................................................................. 11 
`APPENDIX A: Dear Healthcare Provider Letter........................................................................... 14 
`APPENDIX B: Dear Pharmacist Letter ......................................................................................... 17 
`APPENDIX C: Journal Information Piece For Rheumatologists or Rheumatology Healthcare Providers
`(including physician assistants and nurse practitioners) ................................................................ 20 
`APPENDIX E: Journal Information Piece For Family Practitioners, General Practitioners, and Internal
`Medicine Specialists ...................................................................................................................... 24 
`APPENDIX F: Journal Information Piece For Emergency Medicine Specialists ......................... 26 
`APPENDIX G: Journal Information Piece For Pharmacists .......................................................... 28 
`APPENDIX H: Screenshot of the Proposed REMS Website ........................................................ 29 
`APPENDIX I: Medication Guide .................................................................................................. 30 
`ATTACHMENT 2: Comments and track changes sent to sponsor on Oct. 26, 2012 ................... 31 
`
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`2
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`Reference ID: 3213370
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` 1
`
`INTRODUCTION
`
`
`This is a review of Pfizer’s proposed Risk Evaluation and Mitigation Strategy (REMS) for
`Xeljanz (Tofacitinib) NDA 20-3214, submitted voluntarily October 25, 2011 (with subsequent
`revisions). The sponsor’s final submission, received on November 5, 2012, is the subject of this
`review.
`
`1.1. BACKGROUND
`
`Regulatory History
`
`Xeljanz (Tofacitinib) 5 mg tablet is proposed for 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 non-
`biologic disease-modifying anti-rheumatic drugs (DMARDs). Tofacitinib is a new molecular
`entity in the Janus kinases (JAKs) family of Kinase Inhibitors.
`
`An Arthritis Advisory Committee meeting was held on May 9, 2012 to discuss in part “potential
`limitations with regard to the safety data presentation and analyses to better determine the safety
`profile of tofacitinib.”1 There were issues with analyzing patients as randomized and not treated,
`which had the potential of a less precise assessment of adverse events (AEs). In addition, there
`was a question of whether the rules for capturing and reporting AEs were consistently applied
`throughout the clinical development program.1 The sponsor was asked to provide additional
`analysis to address these concerns.
`
`The sponsor’s submission dated August 10, 2012 included sensitivity analyses on treatment
`emergent AEs and laboratory data, as well as exposure estimates and incidence rate tables, which
`constituted a major amendment by the Agency. The user fee date was extended to November 21,
`2012.
`
`2.1 Brief Efficacy Overview
`Efficacy was demonstrated in five Phase 3 studies (N=3328) that “assesse[d] the effect of
`tofacitinib on signs and symptoms of disease and physical function, as measured by three
`primary efficacy endpoints (in sequence):
`1. Signs and symptoms as measured by ACR 20 at Month 3 or at Month 6;
`2. Physical function as measured by the HAQ-DI change from baseline at
`Month 3;
`3. Incidence of DAS <2.6 at Month 3 or at Month 6.
`Four studies assessed tofacitinib as an add-on in combination with MTX and in combination with
`traditional DMARDs. One study assessed tofacitinib as a monotherapy, following washout of
`other DMARDs.”2
`
`
`1 Clinical review, Nikolay Nikolov, M.D., DPARP, dated July 6, 2012.
`2 Clinical review, Nikolay Nikolov, M.D., DPARP, June 26, 2012.
`3
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`Reference ID: 3213370
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`2.2 Safety Overview
`Safety data is from two Phase 2 and five Phase 3 studies, covering approximately 3328 patients.
`The overall study population in the development program was representative of the target patient
`population of adult patients with established moderately-to-severely active RA who have had
`inadequate response to at least one DMARD.
`
`As of the sponsor’s safety update in February 2012, 49 deaths were reported in the development
`program; one in the placebo group (N=681), three in comparator adalimumab group (N=204),
`and 45 in tofacitinib-treated patients (N=3328). The breakdown of the 45 tofacitinib-deaths is as
`follows:
` 15 (33%) infections (12 pneumonias)
` 12 (27%) malignancies
` 11 CV (4 cardiac arrest, 2 CVA, 2 arrhythmia, 1 PE, 1 CHF, 1 PHTN)
` 7 other (2 suicides, 2 traumatic, 1 COPD, 1 aspiration, 1 unknown)
`Most of the causes of death are consistent with the profile of immunosuppressive drugs.3
`
`The proposed label, which is in the latter stages of completion, contains a boxed warning for
`serious infections and malignancy.
`Serious infections:
`There is “an increased risk of serious infections, including opportunistic infections, identifying a
`profile of tofacitinib as a major immunosuppressant.
` Serious infections associated with tofacitinib use were common in the RA program with
`pneumonia being the most common (occurring only in tofacitinib-treated patients).
` Tuberculosis occurred only in tofacitinib treated patients in a clearly dose-dependent
`fashion.
` Opportunistic infections were not uncommon and included cases of cryptococcal
`infections, Pneumocystis jiroveci pneumonia, and BK virus encephalitis, which are seen
`exclusively in severely immunocompromized patients.”4
`The proposed label states that:
` patients should be tested for latent tuberculosis before XELJANZ use and during therapy;
` patients invasive fungal infections may present with disseminated, rather than localized
`disease; and
`the risks and benefits of treatment with XELJANZ should be carefully considered prior to
`initiating therapy in patients with chronic or recurrent infection.
`
`
`Malignancies:
`The boxed warning language in the draft label states that 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.
`
`
`
`
`3 Clinical wrap-up meeting slides, Nikolay Nikolob, M.D., DPARP, June 18, 2012.
`4 Clinical review, Nikolay Nikolov, M.D., DPARP, September 26, 2012
`4
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`Reference ID: 3213370
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`“Risk of malignancy, excluding non-melanoma skin cancer, increased numerically in a dose and
`time-dependent fashion (from 0.8 events per 100 pt-yrs for <6 months exposure to 1.4 events per
`100 pt-yrs for >24 months exposure).” 4
`
`Laboratory abnormalities, including hematologic parameters, lipid changes, liver enzymes, and
`serum creatinine elevation:
` Lymphopenia: Dose-dependent sustained progressive lymphopenia occurred (ALC
`<500/mm3), which was also associated with increased risk of infections.3
` Neutropenia: Dose-dependent sustained neutropenia occurred over the first month of
`treatment, none of which were life-threatening (ANC <500/mm3).3
`
`
`
` Hemoglobin: Events of clinically significant hemoglobin decreases and severe or life-
`threatening values were small; however, since anemia may represent an off-target toxicity
`associated with tofacitinib use due to its mechanism of action warrants inclusion of
`hemoglobin monitoring in labeling.2
`
` Lipid changes: Dose-dependent elevations in total, LDL (mean increase by 15%), and
`HDL (mean increase by 10%) cholesterol, were observed during the first 3 months of
`exposure.
`Total cholesterol and LDL responded to lipid-lowering therapy. Few Major Adverse
`Cardiovascular Events (MACE) were observed; the incidence was similar among
`treatment groups and stable over time.3
`
`
`“Gastrointestinal perforations and interstitial lung disease were observed in the clinical trials,
`however the relative risk and role of tofacitinib treatment in the development of these adverse
`events is not well defined.” 4
`
`3 MATERIAL REVIEWED
`The following REMS-related materials were reviewed:
`
`
` Proposed REMS submitted October 25, 2011
` Medical Officer Wrap-Up Meeting slides, June 18, 2012, Nikolay Nikolov, M.D.,
`Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)
` DRISK REMS Interim Comments dated July 17, 2012, October 24, 2012, October
`31, 2012, and November 5, 2012
` Clinical reviews, Nikolay Nikolov, M.D., DPARP, September 26, 2012 and July 6,
`2012, and June 26, 2012
` Revised proposed REMS amendments submitted October 2 and October 29, 2012
` DRISK Final REMS review, ACTEMRA (tocilizumab), Kathryn O’Connell, M.D.,
`Ph.D., Medical Officer, January 2, 2010.
`
`4
`
`RESULTS OF REVIEW OF PROPOSED REMS
`
`4.1 Need for a REMS
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`The sponsor voluntarily submitted a proposed REMS with the NDA on October 25, 2011.
`According to pre-NDA meeting minutes, there were no questions from the sponsor specific to
`REMS or discussion pertaining to risk management or a proposed REMS. DRISK and DPARP
`determined that a REMS consisting of a Medication Guide, communication plan and a timetable
`for submission of assessments is necessary to ensure that the benefits of tofacitinib outweigh the
`risks of serious infections, including opportunistic infections and tuberculosis, malignancy,
`increase in cholesterol, and decrease in blood counts. This approach is consistent with the initial
`REMS development approach taken with Actemra (tocilizumab), a Human Interleukin-6
`Receptor Inhibitor indicated for the treatment of Rheumatoid Arthritis and Systemic Juvenile
`Idiopathic Arthritis. The adverse event profile of tofacitinib is similar to that of Actemra and
`other DMARDs.
`
`The communication plan will be directed toward rheumatologists and rheumatology healthcare
`providers, infectious disease specialists
`, family practitioners,
`general practitioners, internal medicine specialists, and emergency medicine specialists who may
`prescribe Xeljanz and/or treat serious risks associated with Xeljanz, as well as pharmacists. The
`communication plan will consist of a Dear Healthcare Provider Letter, a Dear Pharmacist Letter,
`and dissemination of information through certain professional societies’ scientific meetings and
`journals.
`
`4.2 Relevant REMS Background
`
`DRISK reviewed the proposed REMS and had interim comments (Set #1) dated July 17, 2012
`that specifically addressed the following:
`
`
` Revision of the REMS goals
` Broadening the audience of the communication plan
` Requesting submittal of the Dear Healthcare Provider Letters and Dear Pharmacist
`Letters for review
` Addition of a REMS website
`
`
`DRISK subsequently reviewed the October 2, 2012 REMS amendment and met with DPARP to
`discuss and gain further clarification and agreement on certain aspects of the REMS.5 Interim
`comments (Set #2) sent October 24, 2012 addressed:
` Additional revision of the REMS goals
` Removal of
`prescribers in the communication plan
`
` from the targeted
`
`
`5 Before the second set of comments was sent to the sponsor, further clarifications were made after discussion with
`DPARP:
` Revision to the clarification of the risks to be included within the REMS
` Revision of the DHCP Letters and Journal Information Pieces to change the header of the following
`language from “Contraindication” to “Limitation of Use”, which is consistent with the most recent label:
`- XELJANZ should not be used in combination with biologic DMARDs or potent
`immunosuppressants such as azathioprine and cyclosporine.
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`6
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`Reference ID: 3213370
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`(b) (4)
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`(b) (4)
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`o Clarification of the risks to be included within the REMS:
`
`— Serious and other important infections
`— Changes in laboratory parameters. such as decreases in neutrophil cotmts.
`increases in
`(b) “)cholesterol M“). decreases in
`hemoglobin levels. and
`(b) ‘4).
`— The risks of gastrointestinal perforation as well as malignancies and other
`lymphoproliferative disorders are not required to be included in the REMS and
`can be addressed via labeling.
`Editorial track changes to the REMS document and the attached materials.
`Addition of a survey of pharmacists’ knowledge and understanding of the serious risks of
`tofacitinib.
`
`The revised track changes to the REMS document sent to the sponsor on October 26, 2012 are
`appended in Attachment 2 of this review. There were subsequent comments sent to the sponsor
`on November 1. and November 2. 2012 regarding edits to the assessment plan, the REMS
`document and REMS appended materials to remain consistent with labeling.
`
`4.3 Summary of November 5, 2012 Proposed REMS Amendment
`
`4.3.1 REMS Goals
`
`The goal of the XELJANZ REMS is to inform healthcare providers and patients about the
`serious risks associated with XELJANZ treatment.
`
`4.3.2 REMS Elements
`
`4.3.2.1 Medication Guide
`
`In accordance with 21 CFR 208.24, a Medication Guide will be included in each XELJANZ
`package. This Medication Guide should be dispensed to each patient by the pharmacy with each
`XELJANZ prescription. The Medication Guide will also be available via sales representatives.
`the XELJANZ patient and professional websites, the XELJANZ REMS website, and a toll-free
`product information line.
`
`4.3.2.2 Communication Plan
`
`Pfizer will implement a communication plan to healthcare provist to support the
`implementation of the REMS. The communication plan will include:
`
`1. A Dear Healthcare Provider Letter (DHCPL)
`2. A Dear Pharmacist Letter
`
`3. Dissemination of information through professional societies’ scientific meetings and
`journals
`4. REMS website
`
`The DHCPL and Dear Pharmacist Letter will include information regarding the serious risks
`associated with XELJANZ and will be distributed twice annually for three years to pharmacists
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`Reference ID: 321 3370
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`and prescribers likely to prescribe XELJANZ or potential adverse effects associated with
`XELJANZ by traditional and electronic mail within 60 days of product approval.
`
`Pfizer will distribute the letters 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, and pharmacists.
`
`Pfizer will display journal information pieces, for two 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).
`
`In addition, printed journal information pieces will be disseminated quarterly for three years
`following product approval to the following professional societies for wider dissemination in the
`following scientific journals: The Rheumatologist, Arthritis &Rheumatism, Arthritis Care &
`Research, Clinical Infectious Disease, 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.
`
`All of the REMS materials will be available through the XELJANZ program website
`www.XELJANZREMS.com, which will exist for 3 years following approval of the REMS.
`
`See the following Attachments for the final XELJANZ REMS:
` Attachment 1: Xeljanz REMS document
`- Appendix A: Dear HealthCare Provider Letter
`- Appendix B: Dear Pharmacist Letter
`- Appendix C: Journal Information Piece For Rheumatologists or
`Rheumatology Healthcare Providers (including physician assistants and nurse
`practitioners)
`- Appendix D: Journal Information Piece For Infectious Disease Specialists
`- Appendix E: Journal Information Piece For Family Practitioners, General
`Practitioners, and Internal Medicine Specialists
`- Appendix F: Journal Information Piece For Emergency Medicine Specialists
`- Appendix G: Journal Information Piece For Pharmacists
`- Appendix H: Screenshot of the Proposed REMS Website
`- Appendix I: Medication Guide (The Medication Guide was reviewed
`separately and is not appended here.)
` Attachment 2: Comments and track changes sent to sponsor on Oct. 26, 2012
`
`
`
`4.3.2.3 Timetable for Submission of Assessments
`
`Pfizer will submit REMS Assessments to the FDA by at 18 months, by 3 years and in the 7th
`years from the date of approval of the REMS. To facilitate inclusion of as much information as
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`possible while allowing reasonable time to prepare the submission, the reporting interval covered
`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.
`
`4.3.3 REMS Assessment Plan
`
`Pfizer will submit REMS Assessments to FDA at 18 months, by 3 years and 7 years from the
`date of REMS approval.
`The following information needed for assessments is included in the REMS supporting
`document:
`
`
`1. A survey of the patients’ knowledge and understanding of the serious risks of tofacitinib.
`
`
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`
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`2. A survey of the prescribers’ knowledge and understanding of the serious risks of
`tofacitinib.
`
`3. A survey of the pharmacists’ knowledge and understanding of the serious risks of
`tofacitinib.
`
`4. An assessment and conclusions regarding the success of the REMS in meeting the stated
`goals.
`
`5. An assessment of the communication plan including:
`
`a. The source(s) of the list of healthcare professionals to whom the DHCPL, Dear
`Pharmacist Letter are distributed
`b. Journal information pieces published, including date and journal name, volume, and
`issue.
`c. The date of launch of the communication plan (DHCPL, Dear Pharmacist Letter,
`website, and journal information pieces)
`d. The number of recipients of the DCHP and Dear Pharmacist letters
`e. Date(s) of distribution of the DHCP and Dear Pharmacist letters
`f. The number of returned and refused letters
`
`
`DISCUSSION AND CONCLUSION:
`
`5
`
`DRISK and DPARP agree that a REMS consisting of a Medication Guide and communication
`plan is necessary to ensure that the benefits of tofacitinib outweigh the risks, and that prescriber,
`pharmacist, and patient knowledge should be assessed.
`
`Pfizer’s REMS proposal for XELJANZ addresses the requirements stipulated by FDA. The
`proposed REMS for XELJANZ includes a communication plan with a DHCPL, a Dear
`
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`Reference ID: 3213370
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`Pharmacist letter, (Essa-nation of information through professional societies’ scientific
`meetings andjoumals, and a REMS website.
`
`DRISKfindsflleproposedREMSforXEIJANZtobeaccepmble andrecommendsapprovalof
`thisREMS.
`
`10
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`Reference ID: 3213370
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KENDRA C WORTHY
`11/06/2012
`
`CLAUDIA B MANZO
`11/06/2012
`concur
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`Reference ID: 3213370
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`

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`
`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF DRUG EVALUATION II
`DIVISION OF PULMONARY, ALLERGY, AND RHEUMATOLOGY PRODUCTS
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`
`
`
`
`203214
`Xeljanz (tofacitinib), Tablets
`Pfizer
`Sally Seymour, MD, Deputy Director for Safety
`October 25, 2012
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`
`NDA#:
`Products:
`APPLICANT:
`FROM:
`DATE:
`
`
`Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require
`the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such
`a strategy is necessary to ensure that the benefits of the drug outweigh the risks
`[section 505-1(a)]. Section 505-1(a)(1) provides the following factors:
`
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to the
`drug and the background incidence of such events in the population likely to use the
`drug;
`(F) Whether the drug is a new molecular entity (NME).
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS is necessary for Xeljanz (tofacitinib) to ensure
`that the benefits of the drug outweigh the risks of serious infections, including opportunistic
`infections, tuberculosis, malignancy, increase in cholesterol, and decrease in blood counts. In
`reaching this determination, we considered the following:
`
`A. The estimated number of patients in the United States with rheumatoid arthritis (RA) is 1.5
`million. This estimate is based on data published in Arthritis Rheum. 2010 Jun;62(6):1576-
`82.
`
`
`B. RA is a chronic systemic progressive disease associated with synovial inflammation resulting
`in joint pain and swelling, autoantibody production (rheumatoid factor and anti-citrullinated
`protein antibodies), bone erosions, joint space narrowing and joint destruction, and systemic
`features, including inflammation, cardiovascular, pulmonary, musculoskeletal, and other
`manifestations. Sustained RA activity results in irreversible joint destruction, functional
`impairment and increased morbidity and mortality, and significantly impacts society and the
`health care system.
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`Reference ID: 3213341
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`C. Compared with placebo, tofacitinib has been shown to be effective on signs and symptoms
`and physical function in patients with established moderately-to-severely active RA, both as
`a monotherapy and in combination with methotrexate or other traditional disease-modifying
`anti-rheumatic drugs (DMARDs)
`
`
`D. Tofacitinib is expected to be used alone or in a combination with methotrexate or other non-
`biologic DMARDs in patients with moderate to severe active rheumatoid arthritis who have
`had an inadequate response or intolerance to methotrexate. The expected duration of therapy
`with tofacitinib is chronic and potentially life-long.
`
`
`E. The review of tofacitinib NDA identified several areas of major safety concerns potentially
`associated with tofacitinib administration in patients with rheumatoid arthritis:
`
`Malignancy: An increased risk of solid and hematologic malignancies, including
`lymphoproliferative disorder (LPD) was noted in the tofacitinib program. Malignancy was
`numerically higher in the tofacitinib group compared to placebo. Malignancy increased with
`prolonged tofacitinib exposure (from 0.8 events per 100 pt-yrs for <6 months exposure to 1.4
`events per 100 pt-yrs for >24 months exposure). Seven cases of LPD occurred in the overall
`RA development program as of May 2012, all in tofacitinib-treated patients. Two of the cases
`occurred in highly atypical locations (CNS and breast). Five lymphoma cases in 218 (2.3%)
`renal transplant patients who had received 15 mg BID. Lymphomas occurred in the highest
`dose group (3 of 8, 37%) of the chronic toxicology study in monkeys.
`
`
`
`Serious Infections: An increased risk of serious infections, including opportunistic infections,
`was noted in the tofacitinib program, identifying a profile of tofacitinib as a major
`immunosuppressant. Serious infections associated with tofacitinib use were common in the
`RA program with pneumonia being the most common (occurring only in tofacitinib-treated
`patients). Tuberculosis occurred only in tofacitinib treated patients in a clearly dose-
`dependent fashion. Opportunistic infections were not uncommon and included cases of
`cryptococcal infections, Pneumocystis jiroveci pneumonia, and BK virus encephalitis, which
`are seen exclusively in severely immunocompromized patients.
`
`Increased cholesterol: Dose-dependent sustained elevations in total, LDL, and HDL
`cholesterol were noted in the tofacitinib program. Total and LDL cholesterol levels reversed
`with lipid-lowering therapy. These lipid abnormalities did not appear to translate into
`increases in cardiovascular events.
`
`Decreased blood counts: Dose-dependent sustained neutropenia and progressive
`lymphopenia were noted in the tofacitinib program. Severe lymphopenia was also associated
`with increased risk of infections.
`
`In addition to malignancy, serious infections, increased cholesterol, and decreased blood
`counts, tofacitinib is associated with elevation in liver enzymes, elevation in serum
`creatinine, and gastrointestinal perforations.
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`F. Xeljanz (tofacitinib) is a new molecular entity.
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`Reference ID: 3213341
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`Xeljanz (tofacitinib) is a novel product (new molecular entity) and is a new oral disease
`modifying anti-rheumatic drug (DMARD). Consequently, this novel product may be widely
`used. These factors make it important for healthcare providers to be appropriately informed
`about the drug’s serious risks. Similarly, because of the drug’s novelty and anticipated chronic
`use, potentially life-long, patients should also be informed about the serious risks and their
`understanding of the risks should be assessed.
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`In accordance with section 505-1 of FDCA and under 21 CFR 208, FDA has determined that a
`Medication Guide is required for Xeljanz (tofacitinib). FDA has determined that Xeljanz
`(tofacitinib) poses a serious and significant public health concern requiring the distribution of a
`Medication Guide. The Medication Guide is necessary for patients’ safe and effective use of
`Xeljanz (tofacitinib). FDA has determined that Xeljanz (tofacitinib) is a product that has serious
`risks (relative to benefits) of which patients should be made aware because information
`concerning the risks could affect patients’ decisions to use, or continue to use Xeljanz
`(tofacitinib).
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`Additionally, FDA has determined that a Medication Guide is necessary as an element of the
`REMS because maintaining the Medication Guide as part of labeling will not be adequate to
`address the serious and public health concern of adequately informing patients about the serious
`risks of Xeljanz (tofacitinib).
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`FDA has also determined that a communication plan is necessary to ensure that healthcare
`providers are adequately informed about the serious risks of Xeljanz (tofacitinib).
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`The elements of the REMS will be Medication Guide, communication plan, and a timetable for
`submission of assessments of the REMS.
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`Reference ID: 3213341
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