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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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`NDA APPROVAL
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`NDA 22-350
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`Bristol-Myers Squibb Company
`Attention: Pamela Smith, M.D.
`Group Director, Global Regulatory Strategy
`P.O. Box 4000
`Princeton, NJ 08543-4000
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`Dear Dr. Smith:
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`Please refer to your new drug application (NDA) dated and received on June 30, 2008, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Onglyza
`(saxagliptin) Tablets, 2.5 mg and 5 mg.
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`We acknowledge receipt of your submissions dated June 30, August 28, September 26, October
`15, 24, 28, and 29, November 3, 14, 19, and 24, and December 2, 15, 16, 23, and 24, 2008, and
`January 21(2), 22, 23, and 26, February 3, 19(2), 24, and 26, March 12 and 16, April 2, 6, 15, 20,
`and 23, May 19 and 27, June 3, 17, and 22, and July 6, 17 (2), 22 (3), 27, 28, and 30 (3), 2009.
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`This new drug application provides for the use of Onglyza (saxagliptin) Tablets, 2.5 mg and 5
`mg, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus.
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`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
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`CONTENT OF LABELING
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`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)] in structured product labeling (SPL) format, as described
`at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm , that
`is identical to the enclosed labeling text for the package insert and patient package insert
`submitted July 30, 2009. Upon receipt, we will transmit that version to the National Library of
`Medicine for public dissemination. For administrative purposes, please designate this
`submission, “SPL for approved NDA 22-350.”
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`

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` NDA 22-350
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`Page 2
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` CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels submitted on June 30, 2008 and July 6 and 17, 2009, 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 22-350.” Approval of this submission by FDA is not required before
`the labeling is used.
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`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
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`We are waiving the pediatric study requirement for ages 0 to 9 years (inclusive) because the
`necessary studies are impossible or highly impracticable (there are too few children in this age
`range with type 2 diabetes mellitus to study).
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`We are deferring submission of your pediatric studies for ages 10 to 16 years (inclusive) for this
`application because this product is ready for approval for use in adults and the pediatric studies
`have not been completed.
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`Your deferred pediatric study required by section 505B(a) of the FDCA is a required
`postmarketing study. The status of this postmarketing study must be reported annually according
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`to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. This required study is listed below.
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`PMR 1493-1: Deferred randomized and controlled pediatric study under PREA to evaluate
`efficacy, safety, and pharmacokinetics of saxagliptin for the treatment of type 2 diabetes mellitus
`in pediatric patients ages 10 to 16 years.
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`Submit all final reports to this NDA. Use the following designator to prominently label all
`submissions:
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`Required Pediatric Assessment(s)
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`Final Report Submission:
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`by June 30, 2015
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` NDA 22-350
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`Page 3
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` POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o) of the 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)).
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`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
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`of embryofetal toxicity observed in a previously submitted study of saxagliptin plus metformin
`in rats, a signal of a serious risk of cardiovascular events, and the serious risks of severe hepatic
`events and hypersensitivity reactions associated with saxagliptin treatment.
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`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 these serious
`risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following studies:
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`PMR 1493-2 Embryofetal development study of saxagliptin and metformin in combination in
`rats. Include saxagliptin monotherapy and metformin monotherapy treatment arms.
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`The timetable you submitted via email on June 29, 2009, states that you will conduct
`this study according to the following timetable:
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`Final Protocol Submission:
`Study Completion:
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`Final Report Submission:
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`by July 31, 2010
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`by September 30, 2010
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`by April 30, 2011
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`PMR 1493-3 Embryofetal development study with of saxagliptin and metformin in combination
`in rabbits. Include saxagliptin monotherapy and metformin monotherapy treatment arms.
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`The timetable you submitted via email on June 29, 2009, states that you will conduct
`this study according to the following timetable:
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`Final Protocol Submission:
`Study Completion:
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`Final Report Submission:
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`by July 31, 2010
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`by September 30, 2010
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`by April 30, 2011
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`PMR 1493-4 An epidemiologic study to compare the risk of severe hepatic events among
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`patients with type 2 diabetes exposed to saxagliptin to the risk in patients exposed to other
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`antidiabetic medications.
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`The timetable you submitted by email on July 22, 2009, states that you will conduct this
`study according to the following timetable:
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`

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` NDA 22-350
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`Page 4
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`Final Protocol Submission:
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`Study Completion:
`Final Report Submission:
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`by January 31, 2010
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`by May 30, 2015
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`by November 30, 2015
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`PMR 1493-5 An epidemiologic study to compare severe hypersensitivity and severe cutaneous
`reactions among patients with type 2 diabetes exposed to saxagliptin and those exposed to other
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`antidiabetic medications.
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`The timetable you submitted by email on July 22, 2009, states that you will conduct this
`study according to the following timetable:
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`Final Protocol Submission:
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`Study Completion:
`Final Report Submission:
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`by January 31, 2010
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`by November 30, 2016
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`by June 30, 2017
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`Finally, there have been signals of a serious risk of cardiovascular events with some
`medications developed for the treatment of type 2 diabetes and available data have not
`definitively excluded the potential for this serious risk with saxagliptin. We have
`determined that only a clinical trial (rather than a nonclinical or observational study) will be
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`sufficient to assess a signal of a serious risk of cardiovascular events with anti-diabetic
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`medications, including saxagliptin, to definitively exclude unacceptable cardiovascular
`toxicity. Therefore, based on appropriate scientific data, FDA has determined that you are
`required to conduct the following:
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`PMR 1493-6 A randomized, double-blind, controlled trial evaluating the effect of saxagliptin on
`the incidence of major adverse cardiovascular events in patients with type 2 diabetes mellitus.
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`The primary objective of this trial is to establish that the upper bound of the 2-sided 95%
`confidence interval for the estimated risk ratio comparing the incidence of major adverse
`cardiovascular events observed with saxagliptin to that observed in the control group is less
`than 1.3. Secondary objectives must include an assessment of the long-term effects of
`saxagliptin on lymphocyte counts, infections, hypersensitivity reactions, liver, bone fracture,
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`pancreatitis, skin reactions, and renal safety. For hypersensitivity reactions, especially
`angioedema, reports should include detailed information on concomitant use of an
`angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. For cases of
`pancreatitis, serum amylase and/or lipase concentrations with accompanying normal ranges
`and any imaging study reports should be included in the narratives.
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`Because renal impairment is an important complication of diabetes, you must ensure that
`there is a minimum of 1 year of exposure for at least 200 saxagliptin-treated patients with
`moderate renal impairment and at least 100 saxagliptin-treated patients with severe renal
`impairment.
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`The timetable you submitted on July 15, 2009, states that you will conduct this trial
`according to the following timetable:
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`

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` NDA 22-350
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`Page 5
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`Final Protocol Submission:
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`Study Completion:
`Final Report Submission:
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`by November 30, 2009
`by July 31, 2015
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`by January 31, 2016
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`Submit the protocols 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:
`
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`• REQUIRED POSTMARKETING PROTOCOL UNDER 505(o)
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`• REQUIRED POSTMARKETING FINAL REPORT UNDER 505(o)
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`• REQUIRED POSTMARKETING CORRESPONDENCE UNDER 505(o)
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`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.
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`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)
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`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.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
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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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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
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`package insert(s), at the time of initial dissemination or publication, accompanied by a Form
`FDA 2253. 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,
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` NDA 22-350
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`Page 6
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`Advertising, and Communications (DDMAC), see
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`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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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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`Suite 12B-05
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`5600 Fishers Lane
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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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`In addition to the standard reporting requirements for an approved NDA, we request that you
`submit as 15-day expedited reports, all postmarketing cases of (1) liver test abnormalities
`accompanied by jaundice or hyperbilirubinemia, (2) opportunistic infections associated with the
`use of saxagliptin, and (3) pancreatitis, regardless of whether these reports are classified as
`serious or unexpected.
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`MEDWATCH-TO-MANUFACTURER PROGRAM
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`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
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`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
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`If you have any questions, call Rachel Hartford, Regulatory Project Manager, at (301) 796-0331.
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`Sincerely,
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` {See appended electronic signature page}
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`Curtis J. Rosebraugh, M.D., M.P.H.
`Director
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`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`

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` NDA 22-350
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`Page 7
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`Enclosures:
` Package Insert
`Patient Package Insert
`Container Label – 2.5mg, 30 tablet bottle
`Container Label – 2.5mg, 90 tablet bottle
` Container Label – 5mg, 10 tablet blister card
` Container Label – 5mg, 30 tablet bottle
` Container Label – 5mg, 30 tablet bottle (sample)
` Container Label – 5mg, 90 tablet bottle
` Container Label – 5mg, 500 tablet bottle
` Carton Label – 5mg, 28 tablet, contains 4 of the 7 tablet wallets (sample)
` Carton Label – 5mg, 30 tablet bottle (sample)
` Carton Label – 5mg, 100 tablet, 10 blister cards with 10 tablets each
` Container/Carton Label – 5mg, 7 tablet wallet (sample)
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`

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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/
`----------------------------------------------------
`
`CURTIS J ROSEBRAUGH
`07/31/2009
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`