CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`201281Orig1s000
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`OTHER ACTION LETTER(S)
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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 201281
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`COMPLETE RESPONSE
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`Boehringer Ingelheim Pharmaceuticals, Inc.
`Attention: Dawn Collette
`Associate Director, Drug Regulatory Affairs
`900 Ridgebury Rd/ P.O. Box 368
`Ridgefield, CT 06877-0368
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`Dear Ms. Collette:
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`Please refer to your New Drug Application (NDA) dated and received January 19, 2011,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, for
`linagliptin and metformin hydrochloride tablets (2.5 mg/500 mg, 2.5 mg/850 mg, and
`2.5 mg/1000 mg).
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`We acknowledge receipt of your amendments dated January 28, February 7, March 11, April 12,
`19 and 27, May 19, June 1 and 13, July 1 and 27, August 3, 17 and 26, September 1, 15 and 21,
`and November 1, 7 and 8, 2011.
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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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`FACILITY INSPECTIONS
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` testing facility for this
`During a recent inspection of the
`application, our field investigator conveyed deficiencies to the representative of the facility.
`Satisfactory resolution of these deficiencies is required before this application may be approved.
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`LABELING
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`We reserve comment on the proposed labeling until the application is otherwise adequate. If you
`revise labeling, your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)]
`in structured product labeling (SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
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`SAFETY UPDATE
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`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
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`Reference ID: 3045232
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`(b) (4)
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`NDA 201281
`Page 2
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`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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`• 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.
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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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`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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`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: 3045232
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`NDA 201281
`Page 3
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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, please contact 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.
`Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Reference ID: 3045232
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`This is a representation of an electronic record that was signed
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`electronically and this page is the manifestation of the electronic
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`signature.
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`MARY H PARKS
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`11/16/2011
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`Reference ID: 3045232
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`Reference ID: 3083109
`Reference ID: 3083109
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