CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202270Orig1s000
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`OTHER ACTION LETTERS
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA 202270
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`COMPLETE RESPONSE
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`Merck Sharp & Dohme Corp.
`Attention: Richard J. Swanson, Ph.D.
`Senior Director, Regulatory Affairs
`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 New Drug Application (NDA) dated September 23, 2010, received
`September 23, 2010, submitted pursuant to section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for JANUMET XR (sitagliptin and extended-release metformin
`hydrochloride fixed-dose combination) Tablets, 100mg/1000mg, 50mg/500mg, and
`50mg/1000mg.
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`We acknowledge receipt of your amendments dated September 30, November 11 and 12,
`December 16 and 23, 2010; and January 10(2), January 21, March 25, April 11, 13, 27, and 29,
`May 6 (2), 18, 27, and 31, June 3, 22, and 30, and July 1 (2), 11, 12 (2), and 18, 2011.
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`We also acknowledge receipt of your amendment dated July 21, 2011, which was not reviewed
`for this action. This amendment contained updated datasets in SAS transport files for the
`complete study report (CSR) for Study 147-00, entitled “A Definitive Bioequivalence Study for
`Sitagliptin/Metformin XR FDC Tablets in Healthy Subjects”.
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`We have completed our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this
`action below and, where possible, our recommendations to address these issues.
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`CLINICAL PHARMACOLOGY
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`Please submit the updated CSR for Study 147-00. You may incorporate applicable sections of
`the amendment dated July 21, 2011 by specific reference as part of your response to the
`deficiencies cited in this letter.
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`FACILITY INSPECTIONS
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`During the pre-approval inspection of the Arecibo, Puerto Rico manufacturing facility on March
`28 through April 14, 2011, our field investigators conveyed deficiencies, which were
`documented on the Form FDA 483 on April 14, 2011, to the representatives of the facility.
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`Reference ID: 2977465
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`NDA 202270
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`Page 2
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`Satisfactory resolution of these deficiencies is required before this application may be approved.
`Specifically:
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`1. Your response to Observation 1A
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`(I'm
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`2. Additionally, the inspection revealed that the facility was not ready to meet the
`(5x4) 22}
`application commitment of using
`Specifically, you could not provide data or procedures to
`M" to the Arecibo facility was not
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`support the use of
`complete at the time of the inspection.
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`SAFETY UPDATE
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`When you respond to the above deficiency, 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.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
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`0 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.
`0 For indications other than the proposed indication, provide separate tables for the
`fiequencies of adverse events occurring in clinical trials.
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`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.
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`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.
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`Reference ID: 2977465
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`NDA 202270
`Page 3
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`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.
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`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
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`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.
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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`In our letter dated December 3, 2010, we notified you that a risk evaluation and mitigation
`strategy (REMS) was required for JANUMET XR (sitagliptin and extended-release metformin
`hydrochloride fixed-dose combination) to ensure the benefits of the drug outweighed the risks of
`acute pancreatitis, including necrotizing pancreatitis. We indicated that your REMS must include
`a Medication Guide and a timetable for submission of assessments of the REMS.
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`We also refer to our April 14, 2011 Supplemental New Drug Application (sNDA) approval
`letters for JANUVIA (sitagliptin), sNDA 021995/S-017 and JANUMET (sitagliptin and
`metformin hydrochloride), sNDA 022044/S-016 that informed you that we were releasing the
`requirement for the approved REMS for those products.
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`We acknowledge receipt of your submission dated December 16, 2010 that included a REMS
`proposal for JANUMET XR (sitagliptin and extended-release metformin hydrochloride fixed-
`dose combination). We have determined that maintaining a Medication Guide as part of the
`approved labeling will be adequate to address the serious and significant public health concern
`and will meet the standard in 21 CFR 208.1. Therefore, a REMS will not be necessary to ensure
`that the benefits of JANUMET XR (sitagliptin and extended-release metformin hydrochloride
`fixed-dose combination) outweigh the risks described above. We will notify you if we become
`aware of new safety information and make a determination that a REMS is necessary.
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`We remind you that the Medication Guide will continue to be part of the approved labeling in
`accordance with 21 CFR 208.
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`OTHER
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`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application. A 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.
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`Reference ID: 2977465
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`NDA 202270
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`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.
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`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
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`If you have any questions, call Raymond Chiang, M.S., Regulatory Project Manager, at (301)
`796-1940.
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`Sincerely,
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`{See appended electronic signature page}
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`Mary H. Parks, M.D.
`Director
`Division of Metabolism and Endocrinology
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Reference ID: 2977465
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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/
`----------------------------------------------------
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`MARY H PARKS
`07/22/2011
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`Reference ID: 2977465
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