`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`NDA 021995/S-010, S-011, S-012 and S-014
`
`Merck Sharp and Dohme Corp.
`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, 2008 (S-010), December 19, 2008 (S-011), February 23, 2009 (S-012) and
`November 13, 2009 (S-014), submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Januvia (sitagliptin) tablets.
`
`We also acknowledge receipt of your submissions dated February 17, 2010 (S-010 and S-011),
`January 6 and 20, and February 17, 2010 (S-012) and December 21 and 31, 2009, and January 5,
`15, 20 and 21, and February 4, 8, 19 and 23, 2010 (S-014).
`
`Your submissions of February 17, 2010 (S-010 and S-011), and January 20, 2010 (S-012),
`constitute a complete response to our January 25, 2010 and December 21, 2009 action letters,
`
`respectively.
`
`The “Prior Approval” supplemental applications S-010, S-011 and S-012 provide 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), for the use of Januvia
`(sitagliptin) as combination therapy with a PPARγ agonist (S-011), and for the use of Januvia in
`combination with insulin, alone or in combination with metformin (S-012). The “Prior
`Approval” supplement S-014 contains proposed safety related labeling changes to the Package
`Insert regarding the risk of pancreatitis as well as a newly created Medication Guide, and a
`proposed Risk Evaluation and Mitigation Strategy (REMS). The Package Insert containing the
`pancreatitis-related changes was approved under supplemental application S-013 on
`December 28, 2009.
`
`We have completed our review of these applications, as amended. They are approved, effective
`on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 2
`
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [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 and the Medication Guide). For administrative purposes,
`please designate this submission, “SPL for approved NDA 021995/S-010, S-011, S-012 and
`S-014”.
`
`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
`
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and container labels that are identical to the enclosed representative
`carton and immediate container labels submitted on February 23, 2010, as soon as they are
`available, but no more than 30 days after they are printed. Please submit these labels
`electronically according to the guidance for industry titled Providing Regulatory Submissions in
`Electronic Format – Human Pharmaceutical Product Applications and Related Submissions
`Using the eCTD Specifications (October 2005). Alternatively, you may submit 12 paper copies,
`with 6 of the copies individually mounted on heavy-weight paper or similar material. For
`administrative purposes, designate this submission “Final Printed Carton and Container Labels
`for approved NDA 021995/S-014”. Approval of this submission by FDA is not required before
`the labeling is used.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a REMS if FDA
`becomes aware of new safety information and makes a determination that such a strategy is
`necessary to ensure that the benefits of the drug outweigh the risks (section 505-1(a)).
`
`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 in section 505-1(b)(3) of the FDCA.
`
`Your proposed REMS, submitted on November 13, 2009, amended on January 5, 15 and 20, and
`February 4, 8 and 19, 2010, and appended to this letter, is approved. The REMS consists of the
`Medication Guide included with this letter and the timetable for submission of assessments of the
`
`REMS.
`
`Your assessment of the REMS should include an evaluation of patients’ understanding of the
`serious risks of Januvia (sitagliptin).
`
`The requirements for assessments of an approved REMS under section 505-1(g)(3) include, in
`section 505-1(g)(3)(B) and (C), requirements for information on the status of any postapproval
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 3
`
`
`study or clinical trial required under section 505(o) or otherwise undertaken to investigate a
`safety issue. You can satisfy these requirements in your REMS assessments by referring to
`relevant information included in the most recent annual report required under section 506B and
`21 CFR 314.81(b)(2)(vii) and including any updates to the status information since the annual
`report was prepared. Failure to comply with the REMS assessments provisions in 505-1(g)
`could result in enforcement action.
`
`We remind you that 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.
`
`Prominently identify submissions containing 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:
`
`
`NDA 021995 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 021995
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`
`NEW SUPPLEMENT FOR (NEW INDICATION FOR USE)
`FOR NDA 021995
`REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`
`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)).
`
`Since Januvia (sitagliptin) was approved on October 16, 2006, we have become aware of “new
`
`safety information” as described above.
`
`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).
`
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 4
`
`
`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 are required to
`conduct the following:
`
`
`1602: A 3-month pancreatic safety study in a diabetic rodent model treated with
`sitagliptin.
`
`The timetable you submitted on January 21, 2010, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`June 15, 2010
`
`March 15, 2011
`
`June 15, 2011
`
`
`
`Submit the protocol to your IND, with a cross-reference letter to this NDA. Submit all final
`reports to your NDA. Prominently identify the submission with the following wording in bold
`capital letters at the top of the first page of the submission, as appropriate:
`
`
`
`• REQUIRED POSTMARKETING PROTOCOL UNDER 505(o)
`
`
`• REQUIRED POSTMARKETING FINAL REPORT UNDER 505(o)
`
`
`• REQUIRED POSTMARKETING CORRESPONDENCE UNDER 505(o)
`
`
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR
`
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
`
`remind you that to comply with 505(o), your annual report must also include a report on the
`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
`submit an annual report for studies or clinical trials required under 505(o) on the date required
`will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
`action.
`
`
`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
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 5
`
`
`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
`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).
`
`
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 6
`
`
`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:
`Package Insert
`Medication Guide
`REMS
`Carton and Container Labeling
`
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21995
`
`Submission
`Type/Number
`--------------------
`SUPPL-12
`
`Submitter Name
`
`Product Name
`
`--------------------
`MERCK CO INC
`
`------------------------------------------
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`
`NDA-21995
`
`SUPPL-14
`
`MERCK CO INC
`
`NDA-21995
`
`SUPPL-11
`
`MERCK CO INC
`
`NDA-21995
`
`SUPPL-10
`
`MERCK CO INC
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`02/26/2010
`
`