CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s013
`
`
` Trade Name:
`
`Xeljanz
`
`
`
`
`Generic Name: Tofacitinib
`
`Pfizer, Inc.
`Sponsor:
`
`
`
`Approval Date: 02/08/2016
`
`
`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:
`
`203214Orig1s013
`
`
`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:
`
`203214Orig1s013
`
`
`APPROVAL LETTER
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`RELEASE FROM REMS REQUIREMENT
`
`NDA 203214/S-013
`
`P F Prism C.V.
`c/o Pfizer Inc.
`500 Arcola Road
`Collegeville, PA 19426
`
`
`Attention:
`
`Alicia Holsey, M.S., RAC
`Senior Manager, Worldwide Safety and Regulatory
`
`Dear Ms. Holsey:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received January
`20, 2016, submitted under section 505(b) for Xeljanz (tofacitinib) Tablets, 5 mg.
`
`We also refer to our REMS Modification Notification letter dated January 13, 2016, and we
`acknowledge receipt of your risk evaluation and mitigation strategy (REMS) assessment dated
`November 6, 2015.
`
`This prior approval supplemental application provides for proposed modification to the approved
`REMS and proposes to eliminate the requirement for the approved REMS for Xeljanz
`(tofacitinib).
`
`We have completed our review of this supplemental application. It is approved, effective on the
`date of this letter.
`
`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.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`The REMS for Xeljanz (tofacitinib) Tablets was originally approved on November 6, 2012,
`
`Reference ID: 3884453
`
`
`

`

`NDA 203214/S-013
`Page 2
`
`and the most recent REMS modification was approved on June 19, 2015. The REMS consists of
`a communication plan and a timetable for submission of assessments of the REMS.
`
`Your proposed modifications consist of elimination of the communication plan, and therefore,
`release from the requirement for a REMS for Xeljanz (tofacinib).
`
`As communicated in the January 13, 2016 REMS Modification Notification Letter, we
`determined a communication plan is no longer necessary to include as an element of the
`approved REMS because the communication plan has been completed and the most recent
`assessment demonstrates that the communication plan has met its goals.
`
`Therefore, because the communication plan is no longer necessary to ensure the benefits of the
`drug outweigh the risks, a REMS is no longer required for Xeljanz (tofacitinib).
`
`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, call Carol F. Hill, Senior Regulatory Health Project Manager for
`Safety, 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
`
`Reference ID: 3884453
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SALLY M SEYMOUR
`02/08/2016
`
`Reference ID: 3884453
`
`
`

`

`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s013
`
`
`RISK ASSESSMENT and RISK MITIGATION
`
`REVIEW(S)
`
`
`
`
`
`
`

`

`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
`
`
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS) MODIFICATION
`
`REVIEW
`
`
`Date:
`
`Reviewer:
`
`Acting Team Leader:
`
`
`January 22, 2016
`
`Erin M. Hachey, Pharm.D.
`Risk Management Analyst
`
`Division of Risk Management (DRISK)
`Jamie Wilkins Parker, Pharm.D., DRISK
`
`Division Director:
`
`Cynthia LaCivita, Pharm.D., DRISK
`
`Drug Name(s):
`
`Xeljanz (tofacitinib)
`
`Therapeutic class:
`
`Janus kinase (JAK) inhibitor
`
`Dosage forms:
`
`5 mg oral tablet
`
`OND Review Division:
`
`Division of Pulmonary, Allergy, and Rheumatology Products
`(DPARP)
`
`Application Type/Number: NDA 203214, Supplement 13
`
`Applicant/sponsor:
`OSE RCM #:
`
`PF Prism CV c/o Pfizer, Inc.
`2015-2179
`
`*** This document contains proprietary and confidential information that should not be released
`to the public. ***
`
`Reference ID: 3876723
`
`
`1
`
`

`

`1. INTRODUCTION
`The purpose of this review is to provide the Division of Risk Management’s (DRISK) evaluation
`of the approved risk evaluation and mitigation strategy (REMS) for Xeljanz (tofacitinib),
`
`NDA 203214, and recommend modifications to the REMS, as appropriate. The evaluation of the
`
`approved REMS in meeting its goals uses the results of the REMS assessment reports submitted
`by PF Prism CV c/o Pfizer. The current REMS for Xeljanz was approved June 19, 2015, and
`
`consists of a communication plan (CP) and a timetable for submission of assessments.
`
`1.1 PRODUCT BACKGROUND
`
`
` Xeljanz (tofacitinib) is a Janus kinase (JAK) inhibitor approved for the treatment of moderate to
`
`
` severe rheumatoid arthritis (RA) in adult patients with an inadequate response or intolerance to
`
`
`methotrexate. The recommended dosage of Xeljanz is one 5 mg tablet administered orally twice
`daily. The dosage should be reduced to 5 mg once daily for patients receiving CYP3A4
`inhibitors, patients with moderate-to-severe renal impairment, and patients with moderate hepatic
`impairment. It is recommended that Xeljanz not be initiated in patients with an absolute
`lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) less than
`1000 cells/mm3, or hemoglobin levels less than 9 g/dL. Dose interruption is recommended for
`management of lymphopenia, neutropenia, and anemia.
`
`The original REMS for Xeljanz was approved on November 6, 2012, and the most recent REMS
`modification was approved on June 19, 2015. The goal of the current REMS is to mitigate the
`risk of serious infections, malignancies, lymphoproliferative disorders, increased cholesterol, and
`low blood cell counts associated with Xeljanz by informing healthcare prescribers and
`pharmacists about these risks. The REMS consists of a CP and a timetable for submission of
`
`assessments. The CP includes a Dear Healthcare Provider Letter (DHCPL) 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, a Dear Pharmacist Letter (DPL), dissemination
`
`of information through professional societies’ scientific meetings and journals, and a Xeljanz
`REMS program website. The timetable for submission of assessments indicates that assessment
`
`reports be submitted at 18 months, 3 years, 5 years, and 7 years from the date of approval of the
`original REMS (November 6, 2012).
`1.2 REGULATORY HISTORY
`
`
`
`
`A brief summary of the key regulatory history relevant to the Xeljanz REMS is listed below, in
`chronological order.
`November 6, 2012: Xeljanz (NDA 203214) was approved for the treatment of moderate-to-
`severe rheumatoid arthritis (RA) in adult patients with an inadequate response or intolerance to
`
`
`methotrexate. The approval included a REMS that consisted of a MG and CP.
`July 11, 2013: Pfizer, Inc. informed the Agency of a change in ownership of NDA 203214.
`August 28, 2013: The Agency issued a REMS Modification Notification Letter which requested
`
`
`the Sponsor submit a proposed REMS modification that reflects the change in ownership for
`
`Xeljanz.
`
`Reference ID: 3876723
`
`
`2
`
`
`

`

`September 25, 2013: The Sponsor submitted S-005, which requested revisions to the labeling to
`incorporate new safety information regarding viral hepatitis and the risk of non-melanoma skin
`cancer associated with Xeljanz and to align with recent labeling changes for the tumor necrosis
`factor (TNF) blockers. This submission also included a proposed REMS modification with
`
`revisions to the MG, DHCPL, DPL, and Journal Information Pieces to align the REMS materials
`with the proposed labeling.
`September 27, 2013: The Sponsor submitted S-006, which included a proposed REMS
`modification based on the August 28, 2013 REMS Modification Notification Letter.
`
`November 8, 2013: The Agency approved S-006, to reflect a change in ownership for Xeljanz.
`
`March 26, 2014: The Agency approved S-005, which included approval of a REMS modification
`
`that revised the MG, DHCPL, DPL, and Journal Information Pieces to incorporate information
`regarding viral hepatitis and the risk of non-melanoma skin cancer associated with Xeljanz.
`May 5, 2014: The Sponsor submitted the 18-month REMS Assessment Report.
`July 2, 2014: DRISK review (dated June 30, 2014) of the 18-month REMS Assessment Report
`
`
`concluded that the REMS Assessment Report was complete and REMS goals were being met.
`August 20, 2014: DRISK REMS Modification Review recommended a REMS modification to
`remove the MG from the REMS, revise the REMS goal to remove “and patients,” remove the
`Survey of Patient Knowledge and Understanding, and revise the REMS assessment plan
`accordingly, based on the DRISK review (dated June 30, 2014) of the 18-month REMS
`Assessment Report.
`
`September 9, 2014: The Agency issued a REMS Modification Notification/REMS Assessment
`Plan Revision Letter, which requested removal of the MG as an element of the REMS.
`November 7, 2014: The Sponsor submitted a proposed REMS modification (S-008) based on the
`September 9, 2014 REMS Modification Notification/REMS Assessment Plan Revision Letter.
`December 19, 2014: The Sponsor submitted S-010 to the Agency, which contained a proposed
`REMS modification to align the REMS appended materials with changes proposed to the
`
`
`prescribing information. The changes to the REMS materials included the addition of a warning
`statement regarding the risk of Herpes Zoster (HZ) in Japanese patients treated with Xeljanz to
`the Serious Infections section of the DHCP letter.
`
`February 11, 2015: The Agency approved S-008, which removed the MG from the REMS. The
`MG remained part of the approved labeling.
`April 20, 2015: The Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) sent
`the Sponsor an e-mail communication to request that the Sponsor withhold distribution of their
`May 2015 DHCP letter mailings prior to the approval of S-010.
`
`June 19, 2015: The Agency approved S-010, which modified the approved REMS and REMS
`appended materials to align with changes to the prescribing information regarding the risk of HZ
`infection in Japanese patients treated with Xeljanz. It also modified the goal to the following:
`The goal of the Xeljanz REMS is to mitigate the risk of serious infections, malignancies,
`lymphoproliferative disorders, and laboratory abnormalities associated with Xeljanz by:
`Informing healthcare prescribers and pharmacists about the above risks.
`x
`
`3
`
`
`Reference ID: 3876723
`
`
`

`

`November 6, 2015: The Sponsor submitted the 3-Year REMS Assessment Report, dated October
`27, 2015.
`January 5, 2016: DRISK review of the 3-year REMS Assessment Report concluded that the
`
`REMS Assessment Report was complete and the REMS goal was being met.
`
`
`January 12, 2016: DRISK REMS modification review concluded that the CP activities were
`complete and a REMS was no longer necessary for Xeljanz.
`January 13, 2016: The Agency sent the Sponsor a REMS Modification Notification letter,
`informing them that a REMS was no longer required for Xeljanz.
`January 20, 2016: The Sponsor submitted S-013 to the Agency, in response to the Agency’s
`January 13, 2016 REMS Modification Notification letter.
`
`2. MATERIALS REVIEWED
`The following is a list of materials used to inform this review:
`
`
`x Worthy K and Tavakoli A. DRISK Final REMS Review for Xeljanz, dated
`November 6, 2012.
`x Booker N. DRISK REMS Modification Review for Xeljanz, dated October 23, 2013.
`x Cvetkovich T. DRISK Review of 18-Month REMS Assessment Report for Xeljanz, dated
`June 30, 2014.
`
`x Wilkins Parker J. DRISK REMS Modification Review for Xeljanz, dated August
`
`20, 2014.
`x Booker N. DRISK REMS Modification Review for Xeljanz, dated December 17, 2014.
`x Tavakoli A. DRISK REMS Modification Review for Xeljanz, dated June 19, 2015.
`x PF Prism CV c/o Pfizer, Inc., 3-Year REMS Assessment Report for Xeljanz, received
`November 6, 2015.
`
`x Auth D. DRISK Review of 3-Year REMS Assessment Report for Xeljanz, dated January
`5, 2016.
`x Hachey E. DRISK REMS Modification Review for Xeljanz, dated January 12, 2016.
`
`x Seymour S. DPARP. REMS Modification Notification letter, dated January 13, 2016.
`x PF Prism CV c/o Pfizer, Proposed Major REMS Modification for Xeljanz, received
`January 20, 2016 (Seq. 0154).
`
`
`3. DRISK EVALUATION OF THE XELJANZ REMS
`
`3.1 CURRENTLY APPROVED REMS
`
`
`The current Xeljanz REMS (dated June 19, 2015) includes a CP and a timetable for submission
`of assessments. The CP currently includes the following components:
`x A Dear Healthcare Provider Letter: will be distributed twice annually for 2 years from
`
`
`the date of initial approval (11/2012), and once within 60 days of the date of the
`modification approval (6/2015), 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.
`
`Reference ID: 3876723
`
`
`4
`
`
`

`

` The initial letter will be distributed within 60 days of product approval. The Prescribing
`
`
`Information and a copy of the Medication Guide will also be distributed in this
`communication.
`x A Dear Pharmacist Letter: will be distributed twice annually for 2 years from the date
`
`of initial approval (11/2012) and once within 60 days of the date of the modification
`
`
`approval (6/2015), through both traditional mailing and electronic mailing. The initial
`
`letter will be distributed within 60 days of product approval.
`x 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 following journals: 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.
`x Xeljanz REMS Website: 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 three
`years following approval of the REMS. The 3-year requirement for the website was
`included in the initial REMS approval; the intent was for the website to remain active for
`
`
`three years immediately following the initial REMS approval, though the REMS did not
`
`
`specify initial.
`
`
`3.2 STATUS OF COMMUNICATION PLAN ACTIVITIES
`The following table summarizes the status of each activity required for the Sponsor under the CP
`element of the REMS:
`
`Activity
`
`REMS Requirement
`
`Distribution of Dear
`Healthcare Provider letters
`
`Distribution of Dear
`Pharmacist letters
`
`Within 60 days of product approval.
`
`
`
`Twice annually for 2 years from the date of initial
`approval
`Once within 60 days of the date of the modification
`approval
`Within 60 days of product approval
`
`
`
`Twice annually for 2 years from the date of initial
`approval
`Once within 60 days of the date of the modification
`
`Complete
`(Y/N)
`Y
`
`Y
`
`Reference ID: 3876723
`
`5
`
`

`

`Dissemination of information
`through professional
`
`societies’ scientific meetings
`and journals
`REMS Website
`
`approval
`
`Display for 2 years following product approval
`
`Disseminate quarterly for 3 years following product
`approval
`
`Y
`
`Y
`
`Exist for 3 years following the initial approval of the
`REMS
` Note: Product approval was November 6, 2012; REMS modification approval was June 19, 2015
`
`
`
`
`
`
`
`
`
` 3.3 RESULTS OF XELJANZ REMS ASSESSMENT REPORTS
`
`The 18-month REMS Assessment Report was submitted on May 5, 2014, and the findings were
`evaluated by DRISK in a review dated June 30, 2014. DRISK concluded that the REMS was
`
`complete and meeting its goal to inform healthcare providers and patients about the serious risks
`
`associated with Xeljanz. Survey results indicated that prescribers, pharmacists, and patients were
`
`reasonably well aware of the risks in the REMS for Xeljanz.
`
`The 3-year REMS Assessment Report was submitted on November 6, 2015, and the findings
`were evaluated by DRISK in a review dated January 5, 2016. DRISK concluded that the REMS
`
`was complete and meeting its goal to inform healthcare prescribers and pharmacists about the
`risk of serious infections, malignancies, lymphoproliferative disorders, increased cholesterol, and
`
`
` low blood cell counts associated with Xeljanz. Survey results indicated that prescribers and
`pharmacists demonstrated knowledge of the risks in the REMS for Xeljanz.
`
`3.4 ANALYSIS OF SAFETY INFORMATION
`
`Based on a discussion with the Medical Officer on November 13, 2015, and e-mail
`
`communication from the Deputy Director for Safety on November 17, 2015, in the Division of
`
`Pulmonary, Allergy, and Rheumatology Products, there have been no identified or emerging
`
`safety issues since the last REMS modification and REMS assessment review that may require
`
`
`continued or new communication within the next six months. They also concur with DRISK
`
`thinking that the CP REMS is no longer necessary to ensure the benefits outweigh the risks for
`Xeljanz.
`
`4. DRISK-RECOMMENDED REMS MODIFICATION
`After review of the Sponsor’s 18-month REMS Assessment Report, 3-year REMS Assessment
`Report, and available safety information, DRISK recommends that the Xeljanz REMS be
`modified to remove the CP as an element of the REMS, and therefore, remove the requirement
`for the REMS.
`In accordance with CDER’s current thinking1, the following conditions must apply when
`
`considering a REMS modification to eliminate a CP from the REMS:
`
`
`
`
`1. All activities for the CP have been completed, and/or the CP activities have been
`assessed at least once; and
`
`
`
` 1 Safety Requirements Team Update, December 18, 2013.
`
`6
`
`
`Reference ID: 3876723
`
`
`

`

`2.
`
` If the CP has been assessed, the goal of the CP has been met and there is no need to
`
`further assess the current CP; If the CP has not been assessed, no assessment of the
`current CP is necessary; and
`
`
`
`3. There are no identified or emerging safety issues that may require continued or new
`communication within the next 6 months; and
`If the REMS includes ETASU, removal of the CP has no implication for those
`elements, and
`5. The CP is no longer necessary as an element of the REMS to ensure that the benefits
`of the drug outweigh the risks.
`The review team has determined that the above conditions have been met for Xeljanz.
`
`4.
`
`5. DISCUSSION
`
`
`5.1 CONSIDERATIONS FOR ELIMINATING A CP FROM THE REMS
`
`
`
`All of the conditions necessary for eliminating a CP from a REMS have been met for Xeljanz.
`Per the REMS document, all requirements for the Sponsor under the CP of the REMS are
`complete as of November 6, 2015, and have been assessed in both the 18-month and 3-year
`REMS Assessment Reports. Based on the findings from the 18-month and 3-year REMS
`Assessment Reports, the review team determined that the goal of the REMS has been met.
`Additionally, further assessment of the current CP is not necessary. There have been no
`identified or emerging safety issues that may require continued or new communication within the
`next six months.
`
`5.2 ASSESSMENT OF WHETHER A REMS IS STILL NECESSARY
`The purpose of the CP for the Xeljanz REMS is to inform healthcare providers about the serious
`risks associated with Xeljanz. The 3-Year REMS Assessment Report confirms that all CP
`activities are complete as of November 6, 2015, and the assessment report demonstrates that
`prescribers and pharmacists are knowledgeable about the REMS risks. Therefore, DRISK and
`
`DPARP concur that a REMS is no longer necessary to ensure the benefits outweigh the risks for
`Xeljanz.
`
`6. CONCLUSION AND RECOMMENDATIONS
`Based on the status of the Communication Plan activities, the REMS assessment findings, and
`available safety data, DRISK believes the CP is no longer necessary to ensure that the benefits of
`Xeljanz outweigh the risks. Therefore, DRISK recommends the Sponsor be sent a REMS
`Modification Notification letter to request the removal of the CP.
`
`Reference ID: 3876723
`
`
`7
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`ERIN M HACHEY
`01/22/2016
`
`CYNTHIA L LACIVITA
`01/22/2016
`Concur
`
`Reference ID: 3876723
`
`
`