CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208026Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`Filing Meeting: September 9, 2015
`NDA 208026
`Drug: Linagliptin and metformin hydrochloride (HCl) extended-release (XR) fixed dose
`combination (FDC)
`Sponsor: Boehringer Ingelheim (BI)
`Date Received: July 27, 2015
`PDUFA date: May 27, 2016
`
`Assessment: From the clinical standpoint, the NDA is fileable.
`
`Background:
`
`This is a 505(b)(1) NDA for linagliptin and metformin hydrochloride XR FDC tablets for once daily
`administration in patients with type 2 diabetes mellitus (T2DM). The proposed indication is 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.
`
`The sponsor cross-referenced the existing clinical safety and efficacy data for linagliptin
`(Trajenta; NDA 201280), combination of linagliptin and metformin HCl immediate release
`(Jentadueto; NDA 201281), and metformin XR (Glumetza; NDA 021748). BI is the NDA holder for
`both Tradjenta and Jentadueto and has obtained a right of reference and full access to use the
`information included within Glumetza NDA.
`
`The sponsor intends to market two strengths of linagliptin/metformin XR FDC tablets, 2.5
`mg/1000 mg and 5 mg/1000 mg. To bridge the efficacy and safety data from three referenced
`NDAs to this FDC, the sponsor submitted results from two pivotal clinical pharmacology studies
`to demonstrate the bioequivalence (BE) between linagliptin/metformin XR FDC tablet strengths
`5/1000 mg and 2.5/1000 mg to the co-administration of individual components in Study 1288.9
`and Study 1288.11, respectively.
`
`The sponsor did not submit Integrated Summary of Efficacy or Integrated Summary of Safety
`(ISS) as only Phase 1 studies have been conducted for this NDA. In lieu of ISS, the sponsor
`provided the most recent Periodic Benefit Risk Evaluation Report (Date of report June 30, 2015;
`covering May 3, 2014 to May 2, 2015) for Jentadueto in Module 5.3.6 to provide updated safety
`information related to combined use of linagliptin and metformin. This is in agreement with our
`pre-NDA meeting responses.
`
`We agreed with sponsor’s Agreed Initial Pediatric Study Plan on June 12, 2015.
`
`Reference ID: 3824279
`
`1
`
`

`

`NDA/BLA Number: 208026
`
`Drug Name: linagliptin and
`metformin hydrochloride
`extended release
`
`Applicant: Boehringer
`Ingelheim
`NDA/BLA Type: 505(b)(1)
`
`Stamp Date: July 27, 2015
`
`On initial overview of the NDA/BLA application for filing:
`
`3.
`
`4.
`
`Content Parameter
`FORMAT/ORGANIZATION/LEGIBILITY
`1.
`Identify the general format that has been used for this
`application, e.g. electronic CTD.
`2. On its face, is the clinical section organized in a manner to
`allow substantive review to begin?
`Is the clinical section indexed (using a table of contents)
`and paginated in a manner to allow substantive review to
`begin?
`For an electronic submission, is it possible to navigate the
`application in order to allow a substantive review to begin
`(e.g., are the bookmarks adequate)?
`5. Are all documents submitted in English or are English
`translations provided when necessary?
`Is the clinical section legible so that substantive review can
`begin?
`LABELING
`7. Has the applicant submitted the design of the development
`package and draft labeling in electronic format consistent
`with current regulation, divisional, and Center policies?
`SUMMARIES
`8. Has the applicant submitted all the required discipline
`summaries (i.e., Module 2 summaries)?
`
`6.
`
`9. Has the applicant submitted the integrated summary of
`safety (ISS)?
`10. Has the applicant submitted the integrated summary of
`efficacy (ISE)?
`11. Has the applicant submitted a benefit-risk analysis for the
`product?
`12. Indicate if the Application is a 505(b)(1) or a 505(b)(2).
`505(b)(2) Applications
`13. If appropriate, what is the relied upon listed drug(s)?
`14. Did the applicant provide a scientific bridge demonstrating
`the relationship between the proposed product and the listed
`drug(s)/published literature?
`15. Describe the scientific bridge (e.g., BA/BE studies)
`DOSE
`16. If needed, has the applicant made an appropriate attempt to
`
`Reference ID: 3824279
`
`2
`
`Yes No NA
`
`Comment
`
`Electronic CTD
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Sponsor submitted
`Clinical Overview in
`Module 2.5 as
`requested; we agreed
`that Clinical
`summaries are not
`required for Module
`2.7
`Not needed for this
`NDA
`Not needed for this
`NDA
`In Clinical Overview
`
`505(b)(1)
`
`x
`
`x
`
`X
`
`

`

`Content Parameter
`determine the correct dosage and schedule for this product
`(i.e., appropriately designed dose-ranging studies)?
`Study Number:
` Study Title:
` Sample Size: Arms:
`Location in submission:
`EFFICACY
`17. Do there appear to be the requisite number of adequate and
`well-controlled studies in the application?
`
`Pivotal Study – BE studies
` Indication:
`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
`18. Do all pivotal efficacy studies appear to be adequate and
`well-controlled within current divisional policies (or to the
`extent agreed to previously with the applicant by the
`Division) for approvability of this product based on
`proposed draft labeling?
`
`19. Do the endpoints in the pivotal studies conform to previous
`Agency commitments/agreements? Indicate if there were
`not previous Agency agreements regarding
`primary/secondary endpoints.
`20. Has the application submitted a rationale for assuming the
`applicability of foreign data to U.S. population/practice of
`medicine in the submission?
`SAFETY
`21. Has the applicant presented the safety data in a manner
`consistent with Center guidelines and/or in a manner
`previously requested by the Division?
`22. Has the applicant submitted adequate information to assess
`the arythmogenic potential of the product (e.g., QT interval
`studies, if needed)?
`23. Has the applicant presented a safety assessment based on all
`current worldwide knowledge regarding this product?
`24. For chronically administered drugs, have an adequate
`number of patients (based on ICH guidelines for exposure1)
`been exposed at the dose (or dose range) believed to be
`efficacious?
`25. For drugs not chronically administered (intermittent or
`short course), have the requisite number of patients been
`exposed as requested by the Division?
`26. Has the applicant submitted the coding dictionary2 used for
`
`x
`
`x
`
`x
`
`Yes No NA
`
`Comment
`
`X
`
`The basis for the
`submission is a
`bioequivalence study.
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`Efficacy for combined
`linagliptin and
`metformin use was
`previously reviewed in
`Jentadueto NDA
`(201281)
`
`Submitted recent
`Periodic Benefit Risk
`Evaluation Report
`
`MedDRA Version
`
`1 For chronically administered drugs, the ICH guidelines recommend 1500 patients overall, 300-600
`patients for six months, and 100 patients for one year. These exposures MUST occur at the dose or dose
`range believed to be efficacious.
`2 The “coding dictionary” consists of a list of all investigator verbatim terms and the preferred terms to
`which they were mapped. It is most helpful if this comes in as a SAS transport file so that it can be sorted
`
`Reference ID: 3824279
`
`3
`
`

`

`Content Parameter
`mapping investigator verbatim terms to preferred terms?
`
`Yes No NA
`
`27. Has the applicant adequately evaluated the safety issues that
`are known to occur with the drugs in the class to which the
`new drug belongs?
`28. Have narrative summaries been submitted for all deaths and
`adverse dropouts (and serious adverse events if requested
`by the Division)?
`
`OTHER STUDIES
`29. Has the applicant submitted all special studies/data
`requested by the Division during pre-submission
`discussions?
`30. For Rx-to-OTC switch and direct-to-OTC applications, are
`the necessary consumer behavioral studies included (e.g.,
`label comprehension, self selection and/or actual use)?
`PEDIATRIC USE
`31. Has the applicant submitted the pediatric assessment, or
`provided documentation for a waiver and/or deferral?
`ABUSE LIABILITY
`32. If relevant, has the applicant submitted information to
`assess the abuse liability of the product?
`FOREIGN STUDIES
`33. Has the applicant submitted a rationale for assuming the
`applicability of foreign data in the submission to the U.S.
`population?
`DATASETS
`34. Has the applicant submitted datasets in a format to allow
`reasonable review of the patient data?
`35. Has the applicant submitted datasets in the format agreed to
`previously by the Division?
`36. Are all datasets for pivotal efficacy studies available and
`complete for all indications requested?
`37. Are all datasets to support the critical safety analyses
`available and complete?
`38. For the major derived or composite endpoints, are all of the
`raw data needed to derive these endpoints included?
`CASE REPORT FORMS
`39. Has the applicant submitted all required Case Report Forms
`in a legible format (deaths, serious adverse events, and
`adverse dropouts)?
`40. Has the applicant submitted all additional Case Report
`Forms (beyond deaths, serious adverse events, and adverse
`drop-outs) as previously requested by the Division?
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`Comment
`16.0 was used for
`reporting Study
`1288.8; Version 17.0
`was used for reporting
`1288.9, 1288.10, and
`1288.11.
`
`CRFs and narratives
`for SAEs and
`discontinuations due
`to AEs from Phase 1
`studies submitted as
`requested
`
`None requested from
`clinical
`
`iPSP agreed on June
`12, 2015
`
`In Clinical Overview
`
`Defer to Clin Pharm
`
`Defer to Clin Pharm
`
`Defer to Clin Pharm
`
`Defer to Clin Pharm
`
`Defer to Clin Pharm
`
`as needed; however, if it is submitted as a PDF document, it should be submitted in both directions
`(verbatim -> preferred and preferred -> verbatim).
`
`Reference ID: 3824279
`
`4
`
`

`

`Content Parameter
`FINANCIAL DISCLOSURE
`41. Has the applicant submitted the required Financial
`Disclosure information?
`
`GOOD CLINICAL PRACTICE
`42. Is there a statement of Good Clinical Practice; that all
`clinical studies were conducted under the supervision of an
`IRB and with adequate informed consent procedures?
`
`Yes No NA
`
`Comment
`
`x
`
`x
`
`All clinical
`investigators listed for
`BE studies are
`employees of BI
`
`IS THE CLINICAL SECTION OF THE APPLICATION FILEABLE? ___Yes_____
`
`The application is fileable pending Clinical Pharmacology review of the datasets submitted.
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-
`day letter.
`
` The hyperlinks to the safety narratives for subjects with serious adverse events and adverse
`events leading to discontinuation from Phase 1 studies provided in Table 5.4: 3 of Clinical
`Overview are not correctly linked to narratives. Please resubmit the table with correct
`hyperlinks to facilitate review.
`
`Hyon (KC) Kwon
`Reviewing Medical Officer
`
`Lisa Yanoff
`Clinical Team Leader
`
`September 24, 2015
`Date
`
`September 24, 2015
`Date
`
`Reference ID: 3824279
`
`5
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HYON J KWON
`09/24/2015
`
`LISA B YANOFF
`09/24/2015
`
`Reference ID: 3824279
`
`

`

`CLINICAL REVIEW
`
`Application Type 505 (b)(1)
`Application Number(s) NDA 208026
`Priority or Standard Standard
`
`July 27, 2015
`Submit Date(s)
`July 27, 2015
`Received Date(s)
`PDUFA Goal Date May 27, 2016
`Division / Office DMEP/ODE 2
`
`Reviewer Name(s) Hyon J. Kwon
`Review Completion Date May 17, 2016
`
`Established Name Linagliptin/metformin HCL
`(Proposed) Trade Name Jentadueto XR
`Therapeutic Class DPP4 inhibitor and biguanide
`Applicant Boehringer Ingelheim
`
`Formulation(s) Linagliptin/metformin HCL ER
`FDC oral tablets at dosages of
`5 mg/1000 mg, 2.5 mg/1000
`mg
`Dosing Regimen Once daily
`Indication(s) As an adjunct to diet and
`exercise to improve glycemic
`control in adults with type 2
`diabetes mellitus when
`treatment with both linagliptin
`
`Reference ID: 3933019
`
`

`

`and metformin is appropriate
`Intended Population(s) Adults with type 2 diabetes
`mellitus
`
`Reference ID: 3933019
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT..........................................7
`1.1 Recommendation on Regulatory Action ..............................................................7
`1.2 Risk Benefit Assessment .....................................................................................7
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ....8
`1.4 Recommendations for Postmarket Requirements and Commitments.................8
`INTRODUCTION AND REGULATORY BACKGROUND .........................................8
`2.1 Product Information .............................................................................................8
`2.2 Currently Available Treatments for Proposed Indications....................................9
`2.3 Availability of Proposed Active Ingredient in the United States .........................10
`2.4
`Important Safety Issues With Consideration to Related Drugs..........................10
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ...........11
`2.6 Other Relevant Background Information ...........................................................11
`3 ETHICS AND GOOD CLINICAL PRACTICES........................................................11
`3.1 Submission Quality and Integrity .......................................................................11
`3.2 Compliance with Good Clinical Practices (GCP) ...............................................11
`3.3 Financial Disclosures.........................................................................................11
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES...........................................................................................................12
`4.1 Chemistry Manufacturing and Controls .............................................................12
`4.2 Clinical Microbiology ..........................................................................................12
`4.3 Preclinical Pharmacology/Toxicology ................................................................12
`4.4 Clinical Pharmacology .......................................................................................13
`5 SOURCES OF CLINICAL DATA.............................................................................14
`5.1 Tables of Studies/Clinical Trials.........................................................................14
`5.2 Review Strategy.................................................................................................14
`5.3 Discussion of Individual Studies/Clinical Trials..................................................15
`6 REVIEW OF EFFICACY ..........................................................................................15
`Efficacy Summary .......................................................................................................15
`6.1
`Indication ...........................................................................................................15
`7 REVIEW OF SAFETY..............................................................................................15
`Safety Summary..........................................................................................................15
`7.1 Methods .............................................................................................................16
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ..........................................16
`7.2 Adequacy of Safety Assessments .....................................................................16
`7.3 Major Safety Results..........................................................................................16
`7.3.1 Deaths.........................................................................................................16
`
`Reference ID: 3933019
`
`3
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`7.3.2 Nonfatal Serious Adverse Events................................................................16
`7.3.3 Dropouts and/or Discontinuations ...............................................................17
`8 POSTMARKET EXPERIENCE................................................................................17
`
`9 APPENDICES..........................................................................................................18
`9.1
`Literature Review/References ...........................................................................18
`9.2
`Labeling Recommendations ..............................................................................18
`
`Reference ID: 3933019
`
`4
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`Table of Tables
`
`Table 1: Study 1288.9 – Bioequivalence Evaluations for 5/1000 mg of
`Linagliptin/Metformin Dose..............................................................................13
`Table 2: Study 1288.11 – Bioequivalence Evaluations for 5/2000 mg of
`Linagliptin/Metformin Dose..............................................................................14
`
`Reference ID: 3933019
`
`5
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`Table of Figures
`No table of figures entries found.
`
`Reference ID: 3933019
`
`6
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`1 Recommendations/Risk Benefit Assessment
`This document contains the clinical efficacy and safety review for NDA 208-026 which
`seeks approval of a new linagliptin and metformin extended release fixed-dose
`combination product (linagliptin/metformin XR) for the treatment of patients with type 2
`diabetes mellitus. The proposed indication is 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
`
`1.1 Recommendation on Regulatory Action
`
`I recommend approval of linagliptin/metformin XR for the proposed indication.
`
`1.2 Risk Benefit Assessment
`
`The Applicant is seeking approval of two strengths of the linagliptin/metformin XR FDC
`where one or two tablets are to be administered once daily with a meal, as follows:
`
` Linagliptin/metformin HCl XR 5 mg/1000 mg; one tablet to be given once daily
`with a meal;
` Linagliptin/metformin HCl XR 2.5 mg/1000 mg; two tablets to be given once daily
`with a meal (providing total daily dose of 5 mg of linagliptin and 2000 mg of
`metformin HCL XR).
`
`The clinical efficacy and safety of individual components in the proposed FDC,
`linagliptin and metformin XR, have already been established in the Tradjenta (201-280)
`and Glumetza (021-748) NDA, respectively. The efficacy and safety of linagliptin as
`add-on to metformin therapy have been previously established in the Tradjenta NDA. In
`addition, the efficacy and safety of co-administration of linagliptin and metformin
`immediate release (IR) twice daily compared to individual component have been
`established in Jentadueto NDA (201-281) from the factorial design study. Also, the
`efficacy and safety of once daily metformin XR was comparable to metformin IR twice
`daily in Glumetza NDA.
`
`Therefore, the clinical development for the proposed linagliptin/metformin XR FDC
`product was designed to bridge the existing clinical efficacy and safety data by
`demonstrating bioequivalence (BE) of each FDC tablet to the free combinations of the
`individual components co-administered in healthy volunteers in Phase 1 BE studies.
`The pivotal BE studies (Study 1288.9 and 1288.11) demonstrated that both proposed
`strengths of the linagliptin/metformin XR FDC were bioequivalent to the combination of
`individual components under both fasted and fed conditions.
`
`Reference ID: 3933019
`
`7
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`The safety review of these Phase 1 BE studies or postmarketing safety data was based
`on review of narratives for all subjects who discontinued from the Phase 1 studies due
`to adverse events and who had serious adverse events, most recent postmarketing
`safety data submitted with the application, and data from the 4-month safety update.
`The safety review did not identify any new safety issues with use of the combination.
`We would expect the safety of linagliptin/metformin XR FDC product be similar to
`Jentadueto.
`
`Therefore, the benefit risk profile of linagliptin and metformin XR FDC is favorable for
`approval.
`
`It is generally believed that fixed-dose combinations have the potential to improve
`adherence to therapy by reducing the number of pills needed and simplifying the dosing
`regimen. In theory, once daily FDC would also reduce dosing frequency and may
`increase treatment adherence. The NDA for linagliptin/metformin XR did not provide
`any data to assess adherence; however, I do not believe that these data are needed for
`an approval recommendation.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`None recommended.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`None recommended.
`2 Introduction and Regulatory Background
`This is a new NDA submitted for the fixed-dose combination (FDC) of linagliptin and
`metformin extended release (XR) for the treatment of adults with type 2 diabetes
`mellitus (T2DM). The proposed indication is an adjunct to diet and exercise to improve
`glycemic control in adults with T2DM in whom treatment with both linagliptin and
`metformin hydrochloride is appropriate.
`
`2.1 Product Information
`
`Linagliptin (Tradjenta) is a dipeptidyl peptidase-4 (DPP-4) inhibitor, and prevents the
`degradation of incretin hormones such as glucagon-like polypeptide-1 (GLP-1) and
`glucose-dependent insulinotropic polypeptide (GIP). It was approved for the treatment
`of T2DM in the U.S. on May 2, 2011 (NDA 201-280). The recommended dose of
`linagliptin is 5 mg once daily with or without food.
`
`Reference ID: 3933019
`
`8
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`Metformin is an oral biguanide, which decreases production of hepatic glucose and
`improves insulin sensitivity. It was approved for the treatment of T2DM in the U.S. as
`Glucophage on March 3, 1995 (NDA 20-357). There is no fixed dosage regimen for
`metformin as it is to be individualized on the basis of effectiveness and tolerance while
`not exceeding the maximum recommended daily doses. The maximum recommended
`dose of Glumetza is 2000 mg once daily with food.
`
`Jentadueto, the FDC of linagliptin/metformin immediate release (IR), was approved for
`the treatment of T2DM in the U.S. on January 30, 2012 (NDA 201-281).
`
`There are varying drug-delivery systems for metformin extended-release (XR)
`formulations, such as hydrophilic polymer matrix system (e.g., Glucophage XR), single-
`composition osmotic technology (e.g., Fortamet), and
` polymer-based system
`(e.g., Glumetza). The drug delivery system for this FDC NDA is based
`
`
`
`2.2 Currently Available Treatments for Proposed Indications
`
`T2DM can be treated with a combination of proper diet, exercise, and the following drug
`therapies, either alone or in combination:
`
` Biguanides: metformin (e.g., Glucophage)
` Sulfonylureas (SUs): glyburide (Micronase), glipizide (Glucotrol), glimepiride
`(Amaryl), chlorpropamide (Diabinese), tolazamide (Tolinase)
`Insulin
`
` Glucagon-like peptide-1 (GLP-1) agonists: exenatide (Byetta, Bydureon),
`liraglutide (Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity)
` Thiazolidinediones (TZDs): rosiglitazone (Avandia), pioglitazone (Actos)
` Dipeptidyl peptidase 4 (DPP-4) inhibitors: sitagliptin (Januvia), saxagliptin
`(Onglyza), linagliptin (Tradjenta), alogliptin (Nesina)
` Meglitinides: repaglinide (Prandin), nateglinide (Starlix)
` SGLT2 inhibitors: empagliflozin (Jardiance), dapagliflozin (Farxiga)
` -Glucosidase inhibitor: acarbose (Precose), miglitol (Glyset)
` Pramlintide (Symlin)
` Dopamine agonist: bromocriptine mesylate (Cycloset)
` Bile acid sequestrants: colesevelam (WelChol)
` Various fixed dose combinations of oral therapies (e.g., Janumet, ActoPlus Met,
`Kombiglyze XR, Oseni, Kazano)
`
`T2DM is a heterogeneous disease in both pathogenesis and clinical manifestations.
`Despite the number of treatment options currently available for the treatment of T2DM,
`a substantial proportion of patients either remain under poor glycemic control or
`experience deterioration of glycemic control after an initial period of successful
`treatment with an anti-hyperglycemic agent (AHA). Many of these drug classes may not
`
`Reference ID: 3933019
`
`9
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`be well-tolerated or have safety issues. For example, SUs and insulins are associated
`with a higher risk for hypoglycemia, metformin and GLP-1 agonists are associated with
`gastrointestinal adverse experiences which can limit dose, while metformin and SGLT2
`inhibitors are contraindicated in patients with severe renal impairment. Furthermore,
`progressive beta-cell dysfunction may lead to secondary treatment failure with an anti-
`diabetic regimen over time requiring the addition of other AHAs. For these reasons,
`there continues to be a need for treatment options to improve glycemic control in
`patients with T2DM.
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Linagliptin (NDA 201-280) and metformin (Glucophage, NDA 020-357) have been
`approved for the treatment of T2DM in the U.S. since May 2, 2011 and March 3, 1995,
`respectively. Jentadueto was approved in the U.S. on January 30, 2012.
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`At this time, three other DPP-4 inhibitors aside from linagliptin are currently approved in
`the U.S. (sitagliptin, saxagliptin, and alogliptin). Safety concerns related to DPP-4
`inhibitors as a class include the following:
` Hypersensitivity such as anaphylaxis, angioedema, exfoliative skin conditions,
`urticaria;
` Pancreatitis;
` Hypoglycemia when used with insulin or insulin secretagogue;
` Severe and disabling arthralgia;
` Heart failure for products containing saxagliptin and alogliptin.
`
`Labeled safety concerns with metformin include the following:
` Lactic acidosis: the risk increases with sepsis, dehydration, excessive alcohol
`intake, hepatic insufficiency, renal impairment, and acute congestive heart
`failure;
` Contraindicated in patients with renal impairment (e.g., serum creatinine ≥1.5
`mg/dL for males, ≥1.4 mg/dL for females, or abnormal creatinine clearance);
` Potential for acute alteration of renal function when undergoing radiologic studies
`with intravascular administration of iodinated contrast materials or any surgical
`procedures requiring restricted intake of food and fluids;
` Decrease in Vitamin B12 levels;
` Hypersensitivity;
` Hypoglycemia, in elderly and debilitated patients when calorie intake is deficient,
`or during concomitant use with other glucose-lowering agents (such as
`sulfonylureas and insulin).
`
`Reference ID: 3933019
`
`10
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`On October 11, 2011 and June 26, 2013, DMEP provided written responses to the
`applicant’s meeting request regarding the development of this XR FDC, where we
`agreed that bioequivalence studies comparing co-administration of the individual
`components to the ‘to-be-marketed’ XR FDC for each tablet strength, under fed and
`fasted conditions, would be appropriate to bridge the existing safety and efficacy data
`from studies of Tradjenta, Glumetza, and Jentadueto.
`
`We also provided written responses to the Applicant’s Type C/pre-NDA meeting request
`on January 6, 2015. We agreed that clinical summaries in Module 2.7 or integrated
`summaries (ISE/ISS) were not required as only Phase 1 studies were conducted for this
`NDA. As agreed, the applicant provided a Clinical Overview and narratives for all
`subjects who discontinued from the Phase 1 studies due to adverse events and who
`had serious adverse events. In addition, a 4-month safety update was submitted on
`November 16, 2015 as requested.
`
`2.6 Other Relevant Background Information
`
`None
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`The quality of submission was acceptable. The submission was organized, and
`information was not difficult to find.
`
`3.2 Compliance with Good Clinical Practices (GCP)
`
`All Phase 1 Clinical Pharmacology studies submitted in this application (1288.8, 1288.9,
`and 1288.11) were GCP compliant per the Applicant.
`
`3.3 Financial Disclosures
`
`All clinical investigators of the pivotal Phase 1 BE studies, 1288.11 and 1288.9, were
`full-time employees of the Applicant.
`
`Reference ID: 3933019
`
`11
`
`

`

`Clinical Review
`
`Hyon J Kwon
`NDA 208026
`
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`4.1 Chemistry Manufacturing and Controls
`
`The Office of Pharmaceutical Quality (OPQ) recommended approval of this NDA; see
`OPQ review dated April 18, 2016 for full details. A brief summary is provided here.
`
`The combination product contains immediate release linagliptin and XR of metformin
`HCL by film coating linagliptin
`“m on readily available metformin XR tablet core.
`(5)“)
`
`excipients or impurities in the proposed drug product.
`
`The nonclinical review verified that there are no new
`
`Linagliptin drug coating solution contains arginine
`The metformin ER tablet core uses
`
`“m.
`
`“m
`
`4.2 Clinical Microbiology
`
`No information related to clinical microbiology was included in this supplement.
`
`4.3 Preclinical Pharmacology/Toxicology
`
`No new pharmacology/toxicology information was included in this supplement, and Dr.
`Carlson recommended approval. Please see his review in DARRTS dated May 3,
`201 6.
`
`The nonclinical support for the safety of this FDC product is provided by cross—
`referencing information in the approved drug products, Tradjenta (NDA 201280),
`Jentadueto (NDA 201281 ), and Glumetza (NDA 21-748). There are no existing or new
`pharmacology/toxicology concerns for the drug substances proposed in this FDC
`product.
`
`Reference ID: 3933019
`
`1 2
`
`

`

`Clinical Review
`Hyon J Kwon
`NDA 208026
`Jentadueto XR (linagliptin and metformin hydrochloride extended release)
`
`4.4 Clinical Pharmacology
`
`The applicant aimed to establish the BE between the linagliptin/metformin XR FDC and
`the co-administration of individual components in order to bridge the existing safety and
`efficacy data from linagliptin (Tradjenta), metformin (Glumetza), and
`linagliptin/metformin IR FDC (Jentadueto). In order to achieve this, the applicant
`conducted two pivotal BE studies for two proposed strengths of Jentadueto XR:
`
` Study 1288.9 evaluated the BE of the linagliptin 5 mg/metformin XR 1000 mg
`FDC to co-administration of linagliptin 5 mg and 2 tablets of metformin XR 500
`mg in fasted and fed conditions;
` Study 1288.11 evaluated the BE of 2 tablets of linagliptin 2.5/metformin XR 1000
`mg FDC to co-administration of linagliptin 5 mg and 4 tablets of metformin XR
`500 mg in fasted and fed conditions.
`
`The Applicant’s results from Study 1288.9, using 5/1000 mg FDC of
`linagliptin/metformin ER compared to that of a single-dose combination of individual
`components under fasted and fed conditions are summarized in Table 1.
`
`Table 1: Study 1288.9 – Bioequivalence Evaluations for 5/1000 mg of
`Linagliptin/Metformin Dose
`
`Source: Clinical Overview, Table 2.1.1:2
`
`The results from Study 1288.11, using 2 tablets of 2.5/1000 mg FDC of
`linagliptin/metformin ER compared to that of a single-dose combination of individual
`components