CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 021995/S-013
`
`
`JANUVIA
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`
`
`Sitagliptin
`
`Merck & Co., Inc.
`
`12/28/2009
`
`JANUVIA is indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes
`mellitus.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 021995/S-013
`
`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
`X
`
`
`
`
`X
`
`
`X
`
`
`
`X
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 021995/S-013
`NDA 021995/8-013
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`NDA 021995/S-013
`
`Merck & Co., Inc.
`
`Attention: Richard J. Swanson, Ph.D.
`
`Director, Regulatory Affairs
`
`P.O. Box 1000, UG2C-50
`North Wales, PA 19454-1099
`
`
`Dear Dr. Swanson:
`
`Please refer to your supplemental new drug application (S-013) dated and received
`March 5, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Januvia (sitagliptin) tablets.
`
`
`dated and received
`We also refer to your supplemental new drug application
`November 13, 2009. Your submission of November 13, 2009, also constitutes a complete
`response to our October 16, 2009, action letter for supplemental application S-013.
`
`In addition, we acknowledge receipt of your submissions dated December 3 and 9, 2009.
`
`
`SAFETY LABELING CHANGES
`
`Our letter dated October 16, 2009, notified you, under section 505(o)(4) of the FDCA, of new
`safety information that needs to be included in the labeling for Januvia (sitagliptin) tablets. This
`information pertains to the risk of acute pancreatitis, including necrotizing pancreatitis, with the
`use of Januvia (sitagliptin).
`
`In response to the safety labeling change requirement outlined in our October 16, 2009, action
`
`letter, S-013
` propose the addition of information regarding pancreatitis in the
`Highlights of Prescribing Information section, subsection Important Limitations of Use and
`subsection Warnings and Precautions, as well as in the corresponding subsections of the Full
`Prescribing Information section of the Package Insert. The agreed-upon changes to the language
`included in our October 16, 2009, letter are as follows (additions are noted by underline and
`deletion are noted by strikethrough):
`
`
`
`1. In the section Highlights of Prescribing Information, sub-section Indications and
`
`Usage, Important Limitations of Use, the following has been added:
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 021995/S-013
`
`Page 2
`
`JANUVIA has not been studied in patients with a history of pancreatitis.
`
`(m4)
`
`(1.33 5.1 .
`
`In the section Highlights of Prescribing Information, sub-section Warnings and
`Precautions, the following has been added:
`
`(hm) There have been postmarketing reports of acute pancreatitis,
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If
`pancreatitis is suspected, promptly discontinue JANUVIA.
`
`(m4)
`
`(5.1).
`
`In the section Full Prescribing Information, sub-section 1.2 Imp_ortant Limitations of
`E, the following has been added:
`
`(It) (4)
`
`JANUVIA has not been studied in patients with a history of
`pancreatitis. It is unknown whether patients with a history of pancreatitis are
`at increased risk for the development of pancreatitis while using JANUVIA.
`[See Warnings and Precautions (5.1).]
`M4)
`
`In the section Full Prescribing Information, sub-section 5. Wamings and Precautions,
`the following has been added:
`
`(5) (4)
`
`There have been postmarketing reports of acute pancreatitisa
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in_
`patients taking JANUVIA. After initiation of JANUVIA,
`"’""
`patients should be observed carefully for signs and symptoms
`(m4)
`
`of pancreatitis
`
`. If
`
`pancreatitis is suspected, JANUVIA should promptly be discontinued and
`appropriate management should be initiated. It is unknown whether patients
`with a histogy of pancreatitis are at increased risk for the development of
`pancreatitis while using JANUVIA.
`(m4)
`
`Additional agreed upon changes to the package insert include:
`
`5. Under Adverse Reactionsz Postmarketing Experience (6.2 1, the following has been added:
`
`

`

`
`
` NDA 021995/S-013
`Page 3
`
`
`
`Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria,
`cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson
`syndrome [see Warnings and Precautions (5.4)]; hepatic enzyme elevations; acute
`pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis
`[see Limitations of Use (1.2); Warnings and Precautions (5.1)].
`
`
`6. Under Patient Counseling Information, Instructions (17.1), the following has been added
`as a second paragraph:
`
`
`
`
`
`Patients should be informed that acute pancreatitis has been reported during
`postmarketing use of JANUVIA. Patients should be informed that persistent severe
`abdominal pain, sometimes radiating to the back, which may or may not be
`accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients
`should be instructed to promptly discontinue JANUVIA and contact their physician
`if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].
`
`
`The Package Insert is approved under S-013, effective on the date of this letter, for use as
`recommended in the enclosed, agreed-upon labeling text and with the minor editorial revisions
`listed below.
`
`
`
`1. At the end of the Highlights of Prescribing Information section, remove the reference to the
`FDA-approved patient labeling or Medication Guide, as the Medication Guide has not yet
`been approved for circulation. When the Medication Guide is approved, this text can be re-
`inserted in the PI.
`
`
`
`2. Under Patient Counseling Information (17), remove the reference to the FDA-approved
`patient labeling or Medication Guide (see comment #1 above).
`
`
`
`3. Under Patient Counseling Information, Instructions (17.1), remove the reference to the FDA-
`approved patient labeling or Medication Guide (see comment #1 above).
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the package
`insert [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at
`http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for the
`package insert). For administrative purposes, please designate this submission, “SPL for
`approved NDA 021995/S-013”. Upon receipt, we will transmit that version to the National
`Library of Medicine for public dissemination. We request that the revised labeling approved
`
`today be available on your website within 10 days of receipt of this letter.
`
`
`(b) (4)
`
`

`

`NDA 021995/S—013
`
`Page 4
`
`(5) (4)
`
`RISK EVALUATION AND MITIGATION STRATEGY ggngz
`
`Our October 16, 2009, letter also notified you that, based on new safety information regarding
`the risk of acute pancreatitis, including necrotizing pancreatitis, with use of Januvia (sitagliptin),
`a Risk Evaluation and Mitigation Strategy (REMS) which consists of a Medication Guide and
`timetable for submission of the assessments of the REMS, is required for Januvia (sitagliptin).
`
`(m4)
`
`CARTON AND MMEDIATE CONTAINER LABELS
`
`We acknowledge your November 13, 2009, submission containing draft carton and containe'rm
`labels.
`
`PROMOTIONAL MATERIALS
`
`All promotional materials for your drug product that include representations about your drug
`product must be promptly revised to make it consistent with the labeling changes approved in
`this supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions to
`your promotional materials should include prominent disclosure of the important new safety
`information that appears in the revised package labeling. Within 7 days of receipt of this letter,
`submit your statement of intent to comply with 21 CFR 314.70(a)(4) to the following address or
`by facsimile at 301-847-8444:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`In addition, as required under 21 CFR 314.81(b)(3)(i), you must submit your updated final
`promotional materials, and the package insert(s), at the time of initial dissemination or
`publication, accompanied by a Form FDA 2253, directly to the above address. For instruction on
`completing the Form FDA 2253, see page 2 of the Form. For more information about
`submission of promotional materials to the Division of Drug Marketing, Advertising, and
`
`

`

`
`
` NDA 021995/S-013
`Page 5
`
`
`Communications (DDMAC), see
`
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`
`the letter to both this NDA and to the following address:
`
`
`MedWatch
`
`Food and Drug Administration
`
`5600 Fishers Lane, Room 12B05
`
`Rockville, MD 20857
`
`
`
`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 Mehreen Hai, Ph.D., Regulatory Project Manager, at
`(301) 796-5073.
`
`
`Sincerely,
`
`
`
`
` {See appended electronic signature page}
`
`Mary H. Parks, M.D.
`
` Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
` Enclosure: Package Insert
`
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21995
`
`Submission
`Type/Number
`--------------------
`SUPPL-13
`
`Submitter Name
`
`Product Name
`
`--------------------
`MERCK CO INC
`
`------------------------------------------
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ERIC C COLMAN
`12/28/2009
`Eric Colman for Mary Parks
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`APPLICATION NUMBER:
`NDA 021995/S-013
`NDA 021995/8-013
`
`OTHER ACTION LETTERS
`
`OTHER ACTION LETTERS
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`PRIOR APPROVAL SUPPLEMENT
`COMPLETE RESPONSE – LABELING
`
`
`NDA 21-995/S-013, S-014
`
`
`
`Merck & Co., Inc.
`Attention: Richard J. Swanson, Ph.D.
`Director, Regulatory Affairs
`P.O. Box 1000, UG2C-50
`North Wales, PA 19454-1099
`
`
`Dear Dr. Swanson:
`
`We have received your supplemental new drug application submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act for the following:
`
`Name of Drug Product:
`
`NDA Number:
`
`Supplement number:
`
`Date of supplement:
`
`Date of receipt:
`
`This supplemental application also constitutes a complete response to our October 16, 2009,
`action letter for supplemental application S-013. S-013 proposes the addition of “cutaneous
`vasculitis” and “pancreatitis” to the Postmarketing Experience subsection of the Adverse
`Reactions section of the package insert, and proposes the addition of “inflammation of the
`pancreas” to the patient package insert.
`
`In response to the safety labeling change request outlined in our October 16, 2009, action letter,
`S-014 proposes the addition of information regarding pancreatitis in the Highlights of
`Prescribing Information section, subsection Important Limitations of Use and subsection
`Warnings and Precautions, as well as in the corresponding subsections of the Full Prescribing
`Information section of the package insert. In addition, in accordance with our action letter, this
`submission also contains a Risk Evaluation and Mitigation Strategy (REMS), as well as a newly
`created Medication Guide.
`
`
`Januvia (sitagliptin) Tablets
`
`21-995
`
`S-014
`
`November 13, 2009
`
`November 13, 2009
`
`
`
`

`

`NDA 21-995/S-013, S-014
`Page 2
`
`
`Unless we notify you within 60 days of the receipt date that the application is not sufficiently
`complete to permit a substantive review, we will file the application on January 12, 2010, in
`accordance with 21 CFR 314.101(a).
`
`Please cite the application number listed above at the top of the first page of all submissions to
`this application. Send all submissions, electronic or paper, including those sent by overnight
`mail or courier, to the following address:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Metabolism and Endocrinology Products
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`If you have any questions, please call me at (301) 796-5073.
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`Mehreen Hai, Ph.D.
`Regulatory Project Manager
`Division of Metabolism & Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21995
`
`Submission
`Type/Number
`--------------------
`SUPPL-13
`
`Submitter Name
`
`Product Name
`
`--------------------
`MERCK CO INC
`
`------------------------------------------
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MEHREEN HAI
`12/28/2009
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`
`
`NDA 21-995/S-010, S-011, S-013
`
`
`Merck & Co., Inc.
`Attention: Richard J. Swanson, Ph.D.
`Director, Regulatory Affairs
`P.O. Box 1000, UG2C-50
`North Wales, PA 19454-1099
`
`
`Dear Dr. Swanson:
`
`Please refer to your supplemental new drug applications (sNDAs) dated and received December
`18 (S-010) and 19 (S-011), 2008, and March 5, 2009 (S-013), submitted under section 505(b) of
`the Federal Food, Drug, and Cosmetic Act (FDCA) for Januvia (sitagliptin) tablets.
`
`We acknowledge receipt of your amendments dated April 3, 9, 13, and 14, May 5, June 8, and
`September 25, 2009 (S-010); April 10 and June 8, 2009 (S-011); and April 1, May 4 and 6, and
`September 25, 2009 (S-013).
`
`These “Prior Approval” supplemental applications provide for the use of Januvia (sitagliptin) as
`combination therapy with a PPARγ agonist (S-011) and for the use of Januvia (sitagliptin) in
`combination with metformin and a PPARγ agonist as an adjunct to diet and exercise in adult
`patients with type 2 diabetes mellitus who are inadequately controlled on combination therapy
`with metformin and a PPARγ agonist (S-010).
`
`The “Changes Being Effected in 30 days” supplemental new drug application (S-013) provides
`for the addition of “cutaneous vasculitis” and “pancreatitis” to the Postmarketing Experience
`subsection of the Adverse Reactions section of the package insert, and proposes the addition of
`“inflammation of the pancreas” to the patient package insert.
`
`We have completed the review of your applications and have been unable to reach agreement
`with you regarding the extent and placement of the information about pancreatitis in the product
`label for Januvia (sitagliptin). Therefore, we have determined that we cannot approve these
`applications in their present form. We have described below our reasons for this action and,
`where possible, our recommendations to address these issues.
`
`Sections 505(o)(4) and 505-1 of the FDCA authorize FDA to require holders of approved drug
`and biological product applications to make safety related labeling changes and develop and
`comply with Risk Evaluation and Mitigation Strategies (REMS) based upon new safety
`information that becomes available after approval of the drug or biological product.
`
`
`
`

`

`NDA 21-995/S-010, S-011, S-013
`Page 2
`
`
`Since Januvia (sitagliptin) was approved on October 16, 2006, we have become aware of 88
`cases of pancreatitis associated with the use of sitagliptin in FDA’s Adverse Event Reporting
`System (AERS) database. These include two cases of necrotizing pancreatitis. We consider this
`information to be “new safety information” as defined section 505-1(b)(3) of the FDCA.
`
`SAFETY LABELING CHANGES
`
`In accordance with section 505(o)(4) of the FDCA, we are notifying you that based on the
`new safety information described above, we believe that the new safety information should
`be included in the labeling for Januvia (sitagliptin) as follows:
`
`
`1. In the section Highlights of Prescribing Information, sub-section Indications and
`Usage, Important Limitations of Use, add the following:
`
`JANUVIA has not been studied in patients with a history of pancreatitis.
`Consider other antidiabetic therapies in patients with a history of pancreatitis
`(1.2).
`
`2. In the section Highlights of Prescribing Information, sub-section Warnings and
`Precautions, add the following:
`
`Pancreatitis: Postmarketing reports, including fatal and non-fatal hemorrhagic or
`necrotizing pancreatitis. Discontinue JANUVIA promptly. JANUVIA should not be
`restarted. Consider other antidiabetic therapies in patients with a history of
`pancreatitis (5.1).
`
`3. In the section Full Prescribing Information, sub-section 1.2 Important Limitations of
`Use, add the following:
`
`Based on post-marketing data JANUVIA has been associated with acute
`pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing
`pancreatitis. JANUVIA has not been studied in patients with a history of
`pancreatitis. It is unknown whether patients with a history of pancreatitis are at
`increased risk for pancreatitis while using JANUVIA. Other antidiabetic
`therapies should be considered in patients with a history of pancreatitis.
`
`4. In the section Full Prescribing Information, sub-section 5. Warnings and Precautions,
`add the following:
`Based on post-marketing data, JANUVIA has been associated with acute
`pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing
`pancreatitis. After initiation of JANUVIA, and after dose increases, observe
`patients carefully for signs and symptoms of pancreatitis (including persistent
`severe abdominal pain, sometimes radiating to the back, which may or may not
`be accompanied by vomiting). If pancreatitis is suspected, JANUVIA should
`promptly be discontinued and appropriate management should be initiated. If
`pancreatitis is confirmed, JANUVIA should not be restarted. Consider
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 21-995/S-010, S-011, S-013
`Page 3
`
`
`
`antidiabetic therapies other than JANUVIA in patients with a history of
`pancreatitis.
`
`
`Medication Guide
`
`In addition to the changes described above to the labeling, you should convert your patient
`package insert to a Medication Guide for Januvia (sitagliptin). Your Medication Guide must
`include information about the serious risk of pancreatitis and will be considered part of the
`proposed REMS described below.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`In accordance with section 505-1(a) of the FDCA, we have determined that a REMS is necessary
`for Januvia (sitagliptin) to ensure that the benefits of the drug outweigh the risks based on the
`new safety information described above.
`
`Your proposed REMS must include the following:
`
`Medication Guide: As one element of a REMS, FDA may require the development of a
`Medication Guide as provided for under 21 CFR Part 208. Pursuant to 21 CFR Part 208, FDA
`has determined that Januvia (sitagliptin) 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 Januvia (sitagliptin). FDA has determined that Januvia (sitagliptin) is a
`product for which patient labeling could help prevent serious adverse effects and has a serious
`risk (relative to benefits) of which patients should be made aware because information
`concerning the risk could affect patients’ decisions to use, or continue to use Januvia
`(sitagliptin).
`
`Under 21 CFR 208, you are responsible for ensuring that the Medication Guide is available for
`distribution to patients who are dispensed Januvia (sitagliptin).
`
`Your previously approved patient package insert must be converted to a Medication Guide and
`must be revised to include the new safety information.
`
`Timetable for Submission of Assessments: The proposed REMS must include a timetable for
`submission of assessments that shall be no less frequent than by 18 months, 3 years, and in the
`7th year after the REMS is initially approved. You should specify the reporting interval (dates)
`that each assessment will cover and the planned date of submission to the FDA of the
`assessment. To facilitate inclusion of as much information as 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. For example,
`the reporting interval covered by an assessment that is to be submitted by July 31st should
`conclude no earlier than June 1st.
`
`
`
`
`
`
`

`

`NDA 21-995/S-010, S-011, S-013
`Page 4
`
`
`Your assessment of the REMS should include an evaluation of patients’ understanding of the
`serious risks of Januvia (sitagliptin).
`
`Please note that supplemental application NDA 21-995/S-013 was submitted as a ”Changes
`Being Effected in 30 days” supplement. We will consider this supplement a Prior Approval
`Supplement. The above changes to the proposed labeling cannot be put into effect prior to
`approval of a supplement. An approved supplement is required for these proposed changes prior
`to distributing drug product made with these changes.
`
`In accordance with section 505(o)(4), within 30 days of the date of this letter, you must submit to
`your supplements noted above proposed changes to the approved labeling in accordance with the
`above direction, or notify FDA that you do not believe a labeling change is warranted, and
`submit a statement detailing the reasons why such a change is not warranted. In accordance with
`section 505-1, you must also submit a proposed REMS within 30 days of the date of this letter.
`The submission statement about the safety labeling change and the proposed REMS should be
`included in the same submission.
`
`Your proposed REMS submission includes two parts: a “proposed REMS” and a “REMS
`supporting document.” Attached is a template for the Proposed REMS that you should complete
`with concise, specific information (see Appendix A). Once FDA finds the content acceptable,
`we will include this document and the Medication Guide as attachments to the approval letter
`that includes the REMS. The REMS, once approved, will create enforceable obligations.
`
`The REMS supporting document should be a document explaining the rationale for each of the
`elements included in the proposed REMS (see Appendix B).
`
`The safety labeling changes portion of the supplement should contain the Medication Guide for
`Januvia (sitagliptin). Include labeling in both Microsoft Word format and content of labeling (21
`CFR 314.50(1) in structured product labeling (SPL) format as described at:
`http://www.fda.gov/oc/datacouncil/spl.html.
`
`Under 21 CFR 208.24(d), you are also responsible for ensuring that the label of each container or
`package, where the container label is too small, includes a prominent and conspicuous
`instruction to authorized dispensers to provide a Medication Guide to each patient to whom the
`drug is dispensed, and states how the Medication Guide is provided. The safety labeling changes
`portion of the supplement should contain marked up package or container labels of all strengths
`and formulations with the required statement alerting the dispenser to provide the Medication
`Guide. We recommend the following language dependent upon whether the Medication Guide
`accompanies the product or is enclosed in the carton (for example, unit of use):
`
`
`(cid:131) “Dispense the enclosed Medication Guide to each patient.” or
`(cid:131) “Dispense the accompanying Medication Guide to each patient.”
`
`
`Prominently identify the submission with the following wording in bold capital letters at the top
`of the first page of the submission:
`
`
`
`
`

`

`NDA 21-995/S-010, S-011, S-013
`Page 5
`
`
` NEW SUPPLEMENT FOR NDA 21-995/S-010, S-011, S-013
`PROPOSED REMS
`AND
`SAFETY LABELING CHANGES UNDER 505(o)(4) )-PRIOR APPROVAL
`SUPPLEMENT
`OR
`SAFETY LABELING CHANGES UNDER 505(o)(4)- CHANGE NOT WARRANTED
`
`Prominently identify subsequent submissions related to the proposed REMS and/or the safety
`labeling changes with the following wording in bold capital letters at the top of the first page of
`the submission:
`
`
`SUPPLEMENT NDA 21-995/S-010, S-011, S-013
`PROPOSED REMS-AMENDMENT
`AND/OR
`SUPPLEMENT NDA 21-995/S-010, S-011, S-013
`SAFETY LABELING CHANGES UNDER 505(o)(4) - AMENDMENT
`
`
`If you do not submit electronically, please send 5 copies of your submission.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o) 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
`(section 505(o)(3)(A)).
`
`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 a signal of a serious risk
`of acute pancreatitis, including necrotizing forms associated with the use of Januvia (sitagliptin).
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious
`risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you will be required,
`pursuant to section 505(o)(3) of the FDCA, to conduct the following study if your application is
`approved:
`
`
`1. A 3-month pancreatic safety study in a diabetic rodent model treated with
`sitagliptin.
`
`
`The specific details of this required postmarketing study will be described more fully in the
`approval letter for these applications, if they are approved.
`
`
`
`
`

`

`NDA 21-995/S-010, S-011, S-013
`Page 6
`
`
`SAFETY UPDATE
`
`When you respond to the above deficiencies, include a safety update as described at 21 CFR
`314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical
`studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.
`
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`8. Provide English translations of current approved foreign labeling not previously
`submitted.
`
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take one of the other
`actions available under 21 CFR 314.110. If you do not take one of these actions, we will consider
`your lack of response a request to withdraw the application under 21 CFR 314.65. A
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`
`
`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
`• Present tabulations of the new safety data combined with the original NDA data.
`•
`Include tables that compare frequencies of adverse events in the original NDA with
`the retabulated frequencies described in the bullet above.
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`
`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 21-995/S-010, S-011, S-013
`Page 7
`
`
`resubmission must fully address all the deficiencies listed. A partial response to this letter will
`not be processed as a resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA’s Guidance for Industry -
`Formal Meetings Between the FDA and Sponsors or Applicants, May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`This product may be considered to be misbranded under the Federal Food, Drug, and Cosmetic
`Act if it is marketed with this change before approval of the “Prior Approval” supplemental
`application.
`
`If you have any questions, call Mehreen Hai, Ph.D., Regulatory Project Manager, at
`(301) 796-5073.
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`Mary H. Parks, M.D.
`Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`Enclosures:
`Appendix A – REMS template
`Appendix B – REMS Supporting Document template
`
`
`
`
`
`
`

`

`NDA 21-995/S-010, S-011, S-013
`Page 8
`
`
`
`APPENDIX A: MEDICATION GUIDE REMS TEMPLATE
`
`
`
`Application number TRADE NAME (DRUG NAME)
`
`Class of Product as per label
`
`Applicant name
`Address
`Contact Information
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`
`I. GOAL(S):
`
` List the goals and objectives of the REMS.
`
`II. REMS ELEMENTS:
`
`A. Medication Guide
`
`If a Medication Guide is included in the proposed REMS, include the following:
`A Medication Guide will be dispensed with each [drug name] prescription. [Describe in detail
`how you will comply with 21 CFR 208.24.]
`
`
`B. Timetable for Submission of Assessments
`
`For products approved under an NDA or BLA, specify the timetable for submission of
`assessments of the REMS. The timetable for submission of assessments shall be no less frequent
`than by 18 months, 3 years, and in the 7th year after the REMS is initially approved. You should
`specify the reporting interval (dates) that each assessment will cover and the planned date of
`submission to the FDA of the assessment. To facilitate inclusion of as much information as
`poss