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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`NDA 021995/S-013
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`Merck & Co., Inc.
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`Attention: Richard J. Swanson, Ph.D.
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`Director, Regulatory Affairs
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`P.O. Box 1000, UG2C-50
`North Wales, PA 19454-1099
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`Dear Dr. Swanson:
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`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.
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`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.
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`In addition, we acknowledge receipt of your submissions dated December 3 and 9, 2009.
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`SAFETY LABELING CHANGES
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`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).
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`In response to the safety labeling change requirement outlined in our October 16, 2009, action
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`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):
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`1. In the section Highlights of Prescribing Information, sub-section Indications and
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`Usage, Important Limitations of Use, the following has been added:
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`(b) (4)
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`(b) (4)
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` NDA 021995/S-013
`Page 2
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`JANUVIA has not been studied in patients with a history of pancreatitis.
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` 5.1).
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`(1.
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`2. In the section Highlights of Prescribing Information, sub-section Warnings and
`Precautions, the following has been added:
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`There have been postmarketing reports of acute pancreatitis,
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If
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`pancreatitis is suspected, promptly discontinue JANUVIA.
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` (5.1).
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`3. In the section Full Prescribing Information, sub-section 1.2 Important Limitations of
`Use, the following has been added:
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` 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).]
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` .
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`4. In the section Full Prescribing Information, sub-section 5. Warnings and Precautions,
`the following has been added:
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` There have been postmarketing reports of acute pancreatitis,
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in
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`patients taking JANUVIA. After initiation of JANUVIA,
` patients should be observed carefully for signs and symptoms
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`of pancreatitis
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`. If
`pancreatitis is suspected, JANUVIA should promptly be discontinued and
`appropriate management should be initiated. It is unknown whether patients
`with a history of pancreatitis are at increased risk for the development of
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`pancreatitis while using JANUVIA.
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`Additional agreed upon changes to the package insert include:
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`5. Under Adverse Reactions, Postmarketing Experience (6.2), the following has been added:
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`(b) (4)
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`(b)
`(4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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` NDA 021995/S-013
`Page 3
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`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)].
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`6. Under Patient Counseling Information, Instructions (17.1), the following has been added
`as a second paragraph:
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`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)].
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`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.
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`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.
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`2. Under Patient Counseling Information (17), remove the reference to the FDA-approved
`patient labeling or Medication Guide (see comment #1 above).
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`3. Under Patient Counseling Information, Instructions (17.1), remove the reference to the FDA-
`approved patient labeling or Medication Guide (see comment #1 above).
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`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
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`today be available on your website within 10 days of receipt of this letter.
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`(b) (4)
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` NDA 021995/S-013
`Page 4
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` RISK EVALUATION AND MITIGATION STRATEGY (REMS)
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`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).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`We acknowledge your November 13, 2009, submission containing draft carton and container
`labels.
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`PROMOTIONAL MATERIALS
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`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:
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`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
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`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
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`publication, accompanied by a Form FDA 2253, directly to the above address. For instruction on
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`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
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`(b) (4)
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`(b) (4)
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`(b) (4)
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` NDA 021995/S-013
`Page 5
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`Communications (DDMAC), see
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`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`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
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`the letter to both this NDA and to the following address:
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`MedWatch
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`Food and Drug Administration
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`5600 Fishers Lane, Room 12B05
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`Rockville, MD 20857
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Mehreen Hai, Ph.D., Regulatory Project Manager, at
`(301) 796-5073.
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`Sincerely,
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` {See appended electronic signature page}
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`Mary H. Parks, M.D.
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` Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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` Enclosure: Package Insert
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`Application
`Type/Number
`--------------------
`NDA-21995
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`Submission
`Type/Number
`--------------------
`SUPPL-13
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`Submitter Name
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`Product Name
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`--------------------
`MERCK CO INC
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`------------------------------------------
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
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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/
`----------------------------------------------------
`
`ERIC C COLMAN
`12/28/2009
`Eric Colman for Mary Parks
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`