CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`206073Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`(
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Review
`
`Date:
`
`December 31, 2014
`
`Reviewer(s):
`
`Team Leader:
`
`Division Director
`
`Subject:
`Drug Name(s):
`Therapeutic Class:
`
`Dosage and Route:
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`Naomi Redd, Pharm.D, Acting Team Leader
`DRISK
`Cynthia LaCivita, Pharm.D, Acting Director
`DRISK
`Evaluation of need for a REMS
`Empagliflozin-Linagliptin (Glyxambi)
`Sodium-dependent glucose co-transporter-2 (SGLT2)
`inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor fixed
`dose combination product
`10 mg empagliflozin/5 mg linagliptin and 25 mg
`empagliflozin/5 mg linagliptin tablet once daily/oral
`Application Type/Number: NDA 206073
`Submission Number:
`Orig-1, 0000
`Applicant/sponsor:
`Boehringer Ingelheim Pharmaceuticals, Inc.
`OSE RCM #:
`2014-524 and 2014-527
`
`
`
`
`
`
`
`
`
`*** This document contains proprietary and confidential information ***
`that should not be released to the public
`
`Reference ID: 3681259
`
`

`

`INTRODUCTION
`1
`This review documents the Division of Risk Management’s (DRISK) evaluation of
`whether a risk evaluation and mitigation strategy (REMS) is necessary for empagliflozin-
`linagliptin fixed-dose combination product (NDA 206073, 505 (b)(1) submission
`received by FDA on January 30, 2014). Empagliflozin is a sodium-dependent glucose co-
`transporter-2 (SGLT2) inhibitor and linagliptin is a dipeptidyl peptidase-4 (DPP-4)
`inhibitor. Both products were developed by Boehringer Ingelheim Pharmaceuticals.
`Boehringer Ingelheim Pharmaceuticals is seeking approval for empagliflozin-linagliptin
`fixed-dose combination product as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus (T2DM) when both empagliflozin and
`linagliptin are appropriate.
`
`1.1 Background
`The empagliflozin-linagliptin fixed-dose combination product is formulated as a tablet
`for oral administration and comes in two dosage strengths: 10 mg empagliflozin/5 mg
`linagliptin and 25 mg empagliflozin/5 mg linagliptin. Proprietary name for
`empagliflozin-linagliptin fixed-dose combination product, Glyxambi®, was approved by
`FDA on May 9, 2014. The PDUFA goal date for this application is on January 30, 2015.
`Linagliptin (Tradjenta, NDA 201280) was approved by FDA on May 2, 2011 as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus. The linagliptin label includes warnings for pancreatitis, hypoglycemia (when
`used in combination with insulin or insulin secretagogues), and hypersensitivity
`reactions. Linagliptin in combination with metformin (Jentadueto, NDA 201281) was
`approved by FDA on January 30, 2012 as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus when treatment with both
`linagliptin and metformin is appropriate; it carries a boxed warning for lactic acidosis as
`does the metformin label.
`Empagliflozin (Jardiance, NDA 204629) was approved by FDA on August 1, 2014 as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus. Please refer to DRISK reviews dated November 12, 2013 and July 28, 2014
`including an evaluation of the need for a REMS for empagliflozin. The empagliflozin
`label includes warnings for hypotension, renal impairment, hypoglycemia (when used in
`combination with insulin or insulin secretagogues), genital mycotic infections, urinary
`tract infections, and for increases in low-density lipoprotein cholesterol.
`Tradjenta, Jentadueto, and Jardiance do not have risk evaluation and mitigation strategy
`(REMS). Boehringer Ingelheim Pharmaceuticals did not include a REMS or risk
`management plan in this submission.
`
`1.2 Regulatory History
`Following is the regulatory history, in pertinent part:
`• January 30, 2014: Application received
`• March 30, 2014: Application filing date
`
`
`Reference ID: 3681259
`
`2
`
`

`

`• June 24, 2014: Internal Mid-Cycle meeting. FDA communicated to the sponsor
`the apparent lack of additional efficacy of the empagliflozin and linagliptin 25
`mg/5 mg combination over empagliflozin 25 mg alone in the treatment naïve
`study population.
`• July 8, 2014: External Mid-Cycle meeting
`• October 15, 2014: Internal Late Cycle meeting
`• October 30, 2014: External Late Cycle meeting
`• December 10, 2014: Wrap-up meeting
`• January 30, 2015: PDUFA goal date
`
`2 MATERIALS REVIEWED
`2.1 DATA AND INFORMATION SOURCES
`• Empagliflozin, DRISK Review, dated November 12, 2013 and July 28, 2014.
`• Empagliflozin-linagliptin, submission cover letter, January 30, 2014.
`• Empagliflozin-linagliptin proposed label, January 30, 2014.
`• Empagliflozin-linagliptin Introduction-Summary, January 30, 2014.
`• Empagliflozin-linagliptin mid-cycle communication, July 10, 2014.
`
`3 RESULTS OF REVIEW
`
`3.1 CLINICAL DEVELOPMENT PROGRAM
`The clinical development program included two phase I trials and one pivotal phase III
`trial (Study 1275.1). The phase III trial included a total of 1363 patients with type 2
`diabetes mellitus with and without a background of metformin randomized and followed
`for up to 52 weeks. This trial evaluated the efficacy and safety of two doses of
`empagliflozin/linagliptin combination (empagliflozin10 mg/linagliptin 5 mg and
`empagliflozin 25 mg/linagliptin 5 mg) compared to the individual components. The
`primary endpoint was change in HbA1c after 24 weeks of treatment.
`In patients with background treatment with metformin, the empagliflozin/linagliptin
`combination (both doses) showed greater reduction in HbA1c when compared to the
`individual components (reached statistical significance for all comparisons). However, in
`the treatment naïve population, the empagliflozin 25 mg/linagliptin 5 mg was not
`statistically significantly better than empagliflozin 25 mg alone decreasing HbA1c.
`
`3.2 SAFETY CONCERNS
`No new safety concerns were identified – the observed safety profile is consistent with
`that of each individual product in the combination.
`
`4 CONCLUSIONS AND RECOMMENDATIONS
`The safety profile of the empagliflozin-linagliptin fixed-dose combination product
`identified by the clinical development program is consistent with the profiles of each
`individual product and can be communicated though labeling. DRISK does not
`recommend a REMS at this time.
`
`
`Reference ID: 3681259
`
`3
`
`

`

`If new safety concerns emerge during the review of this application, please include
`DRISK in any discussion regarding selection of a risk management approach.
`
`
`
`
`
`Reference ID: 3681259
`
`4
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMARILYS VEGA
`12/31/2014
`
`CYNTHIA L LACIVITA
`01/02/2015
`Concur
`
`Reference ID: 3681259
`
`