CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
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`APPLICATION NUMBER:
`
`208026Orig1s000
`
`SUMMARY REVIEW
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`Cross Discipline Team Leader Review
`
`Cross—Discipline Team Leader Review
`
`
`Date
`23 May 2016
`Lisa Yanoff, M.D.
`Cross-Disci 0 line Team Leader Review
`Sub'ect
`NDA/BLA # 208026
`A .
`u licant
`
`From
`
`
`
`
` Jentadueto XR/
`
`Boehrin - er In - elheim Pharmaceuticals, Inc.
`27 Jul 2015
`Date of Submission
`
`PDUFA Goal Date
`27 May 2016
`
`Proprietary Name /
`Established
`S ‘
`
`Dosage forms / Strength
`
`Lina li tin and metformin h drochloride extended—release
`
`Oral tablets with the following dosage strengths:
`5 mg linagliptin/ 1000 mg metformin hydrochloride
`extended-release
`
`2.5 mg linagliptin/1000 mg metformin hydrochloride
`extended—release
`
`Proposed 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 and metformin is
`a to riate
`
`Recommended:
`
`A roval
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`Page 1 of 9
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`Reference ID: 3937675
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`Cross Discipline Team Leader Review
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`Cross Discipline Team Leader Review
`1. Introduction
`Boehringer Ingelheim Pharmaceuticals, Inc. is submitting a New Drug Application (NDA)
`#208026 under section 505(b)(1) of the Federal Food, Drug and Cosmetic Act for the fixed-
`combination drug product linagliptin /metformin hydrochloride extended-release for the
`treatment of patients with type 2 diabetes mellitus (T2DM).
`
`The regulatory pathway through section 505(b)(1) is appropriate because the Applicant is the
`sponsor of the linagliptin product (Tradjenta, NDA 201280) and provides a Letter of
`Authorization from the sponsor of the metformin extended-release product (Glumetza, NDA
`021748).
`
`The proposed indication is 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.
`2. Background and Application Overview
`
`The NDA is for linagliptin/metformin extended release, a fixed combination drug [also known
`as a fixed-dose combination (FDC)] of linagliptin, a dipeptidyl peptidase 4 inhibitor (DPP4-i)
`and metformin, the only member of the biguanide class. Both components are approved in the
`U.S. as individual products, and an immediate release formulation of the combination is also
`approved in the U.S. and marketed as Jentadueto. The proposed trade name Jentadueto XR
`has been determined to be acceptable by the Division of Metabolism and Endocrinology
`Products and by the Division of Medication Error and Prevention Analysis and will be used
`interchangeably with the nonproprietary name throughout this memo.
`
`Linagliptin is the third DPP4-i approved in the U.S. Linagliptin improves glycemic control in
`patients with type 2 diabetes mellitus (T2DM) by inhibiting the inactivation of GLP-1 and GIP
`(incretin hormones) and prolonging the incretin effect on beta cells (serum glucose-dependent
`insulin stimulation) and alpha cells (glucagon suppression). GLP-1 in particular has other
`effects that contribute to improved glucose control in diabetics, such as appetite suppression
`and slowing of the rate of gastric emptying. Linagliptin is dosed at 5 mg once daily.
`
`Metformin is effective in decreasing hepatic glucose output and decreasing peripheral glucose
`utilization. Metformin gained a first-line treatment recommendation by the American Diabetes
`Association and other diabetes professional organizations, and is widely used in the treatment
`of T2DM. The Prescribing Information for Glumetza (metformin XR) states that ‘in general,
`clinically significant responses are not seen at doses below 1500 mg per day. However, a
`lower recommended starting dose and gradually increased dosage is advised to minimize
`gastrointestinal symptoms. The starting dose of GLUMETZA is 1000 mg once daily which in
`order to maximize therapeutic efficacy must be taken with food preferably in the evening.
`Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000
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`Cross Discipline Team Leader Review
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`mg once daily with the evening meal. lfglycemic control is not achieved on GL UMEIZA 2000
`mg once daily, a trial ofGL UMEIZA 1000 mg twice daily should be considered. ’
`
`The proposed strengths for Jentadueto XR are 5 mg linagliptin/1000 mg metformin
`hydrochloride extended-release 2.5 mg linagliptin/1000 mg metformin hydrochloride
`extended-release. The proposed dosing regimen is as follows:
`
`0
`
`o
`
`o
`
`in patients currently not treated with metformin, initiate treatment with 5 mg
`linagliptin/1000 g metformin hydrochloride extended-release once daily
`
`(w)
`
`(5)“) total daily starting dose
`In patients already treated with metformin, the
`of JENTADUETO XR is 5 mg linagliptin and a similar total daily dose of metformin
`In patients already treated with TRADJENTA and metformin or JENTADUETO
`switch to JENTADUETO XR containing 5 mg of linagliptin total daily dose and a
`similar total daily dose of metformin
`
`In addition to adequate clinical trial data, approval of an FDC for the treatment of T2DM is
`dependent on demonstration of bioequivalence (BE) of the FDC and the two individual
`components administered together. With demonstration of BB, the precedent within the
`Division of Metabolism and Endocrinology Products for products containing metformin
`combined with another oral antidiabetic agent is to then approve the FDC for either a ‘narrow’
`indication (e.g. patients who are not adequately controlled on a regimen containing meflormin
`or linagliptin, or in patients who are already treated with both linagliptin and metformin) or a
`‘broad’ indication (e.g. when treatment with both linagliptin and meformin is appropriate).
`The narrow indication is typically granted based on clinical trial data showing additional
`placebo-adjusted glycemic lowering from the second drug (e.g. linagliptin) to metformin. To
`allow treatment with the FDC in patients who are treatment naive, the applicant must show
`that the coadministration (or alternatively, the FDC) is more effective than each component
`alone, in patients not treated with either drug prior to the trial, i.e. show contribution of
`claimed effect of each component as per 21CFR 300.50. The typical approach is to conduct a
`factorial study with each of the single agents being compared to the combination; such a study
`was submitted with the original Jentadueto NDA and was used to support the initial approval
`of Jentadueto with the broader indication.
`
`The basis for the request for approval of the proposed (broad) indication for Jentadueto XR is
`the following:
`
`0 Results of the pivotal bioequivalence (BE) studies
`
`0 Clinical comparability between metformin twice daily (Glucophage) and once daily
`(Glumetza) shown in the original NDA for Glumetza
`o The efficacy and safety of co-administration of linagliptin and metformin twice daily
`(Glucophage) as add-on to metformin in the original Tradjenta NDA and as initial
`therapy in the factorial study 1218.46 submitted to support the approval of Jentadueto
`for the ‘broad’ indication
`
`This summary memo contains a high—level overview of the important review findings of the
`NDA. Please see the individual reviews for each discipline for detailed discussions. This
`memo references the following documents.
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`Page 3 of 9
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`Reference ID: 3937675
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`Cross Discipline Team Leader Review
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`Subject
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`Author
`
`Date in DARRTS
`
`Clinical Pharmacology (OCP) Dr. Sang Chung and Dr.
`review
`Mano' Khurana
`
`27 Apr 2016
`
`Chemistry Manufacturing and Team review, Technical
`Controls Quali
`review
`Lead Dr. Suon Tran
`
`18 Apr 2016 (in
`Panorama
`
`Clinical Efficacy and Safety
`Review
`
`Nonclinical review
`' harmacolo 3 Itoxicolo 3
`
`Division of Pediatric and
`Maternal Health consult
`
`Office of Study Integrity and
`Surveillance inspection
`reviews
`
`Dr. Hyon Kwon
`
`18 May 2016
`
`Dr. David Carlson
`
`20 Apr 2016
`
`Dr. Miriam Dinatale
`
`28 Apr 2016
`
`Dr. Li-Hong Paul Yeh
`
`19 Feb 2016, 11 Mar
`2016, 15 Mar 2016
`
`
`
`Division of Medication Error
`Prevention and Analysis
`consult review
`
`Dr. Sarah Vee and Dr.
`Yelena Maslov
`
`29 Apr 2016
`
`Division of Medical Policy
`Programs (DMPP) consult
`review
`
`Team review
`
`5 May 2016
`
`3. CMC
`
`The recommendation from the Office of Pharmaceutical Quality (including the Overall
`Manufacturing Inspection Recommendation) is approval. NDA 201280 Tradjenta (linagliptin),
`by the same applicant, is referenced for all CMC information on the drug substance linagliptin.
`The NDA is cmrently approved and the reference is adequate. NDA 201281 Jentadueto
`(linagliptin/metformin HC1), by the same applicant, is referenced for all CMC information on
`the drug substance metformin HCl. The NDA is currently approved and the reference is
`adequate.
`
`The drug product is a fihn-coated tablet consisting of innnediate release linagliptin and
`extended release metformin BC], with two strengths: 5 mg/1000 mg and 2.5 mg/1000 mg
`linagliptin (immediate release)/metformin hydrochloride (extended release). Please see the
`Quality review for details.
`
`4. Nonclinical Pharmacology/Toxicology
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`Cross Discipline Team Leader Review
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`The nonclinical pharmacology/toxicology reviewer Dr. David Carlson recommends approval
`of this NDA. No new nonclinical information was submitted to support the proposed
`linagliptin and metformin XR FDC tablets. Nonclinical support for the safety of the proposed
`FDC tablets is claimed from cross referencing information in approved drug products. As
`noted above the drug substances in the proposed FDC tablets are identical to those previously
`approved. Nonclinical review of the drug product excipients and specifications independently
`verified that there are no new excipients or impurities in the proposed drug product. Please see
`Dr. Carlson’s review for details.
`5. Clinical Pharmacology/Biopharmaceutics
`
`The clinical pharmacology reviewer Dr. Sang Chung recommends approval of this NDA. The
`applicant conducted two pivotal BE studies because there are two proposed strengths for
`Jentadueto XR under fasted or fed conditions. According to Dr. Chung, BE was demonstrated
`for both strengths of Jentadueto XR referencing corresponding co-administration of Tradjenta
`and Glumetza under both fasted and fed conditions.
`
`The data from these two studies are shown below.
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`Cross Discipline Team Leader Review
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`Source: Clinical Pharmacology review
`
`Dr. Chung noted no concerns with the study methodology. Site inspections were also
`acceptable (see section 11 of this memo). I agree with Dr. Chung that the pivotal BE study
`results support approval of this NDA.
`6. Clinical Microbiology
`
`Please see the Quality review
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`7. Clinical/Statistical- Efficacy
`
`The basis for establishment of efficacy for Jentadueto XR is the previous review and approval
`of Jentadueto. No clinical efficacy i.e. Phase 3 studies were submitted with this NDA.
`
`8. Safety
`
`The basis for the safety evaluation of Jentadueto XR is the previous review and approval of
`Jentadueto. Dr. Kwon’s safety review included review of narratives for all subjects who
`discontinued from the Phase 1 studies due to adverse events and who had serious adverse
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`events, the 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. Please see her review for details.
`
`9. Advisory Committee Meeting
`
`No advisory committee meeting was convened for this sNDA.
`10.
`Pediatrics
`
`Because this product is a new formulation of the combination of linagliptin and metformin
`from that approved previously, the product approval does trigger requirements under the
`Pediatric Research Equity Act (PREA). In keeping with usual practice, the PREA
`requirements for the linagliptin monotherapy product (1766-1 and 1766-2) will apply to the
`NDA for the combination product.
`
`Of note, the Division is considering a release and reissue of the monotherapy PREA PMR
`1766-2 in order to update the PMR description to reflect current agreements regarding protocol
`design (i.e., linagliptin and another antidiabetic product from this sponsor [empagliflozin] both
`on a background of metformin will be compared against a single placebo arm). This trial
`design was agreed upon by the Division and by the Pediatric Review Committee (PeRC) and is
`reflected in the iPSP for NDA 208026.
`
`11.
`
`Other Relevant Regulatory Issues
`
`The Office of Study Integrity and Surveillance (OSIS) conducted an inspection of the
`bioanalytical portion of studies 1288-9 and 1288-11
`This was determined to be acceptable. See review in DARRTS dated 15 Mar 2016.
`
`.
`
`OSIS also conducted an inspection of the bioanalytical portion of studies 1288-9 and 1288-11
`. The final classification for
` is
`voluntary action indicated (VAI). OSIS concluded that data from this study are acceptable for
`review. See review in DARRTS dated 19 Feb 2016.
`
`OSIS also conducted clinical inspection at Boehringer Ingelheim Pharma GmbH & Co, KG,
`Biberach/Riss, where clinical portions of the BE studies were carried out. This inspection also
`found no issues and reported the pivotal BE data are acceptable for review. See review in
`DARRTS dated 11 Mar 2016.
`
`12.
`
`Labeling
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Cross Discipline Team Leader Review
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`Labeling for Jentadueto XR for the most part should follow labeling of the Jentadueto product.
`Two unique issues are as follows:
`
`Compliance with the Pregnancy and Lactation Labeling Rule (PLLR):
`The proposed label for Jentadueto XR differs from the Jentadueto product in that it proposes
`new language to conform to the PLLR format. A consult from the Division of Pediatric and
`Maternal Health was requested by the Division for input on the labeling. Please see Dr.
`Miriam Dinatale’s review in DARRTS. Development of the PLLR language was an evolving
`process and the approved label will contain the final agreed upon language.
`
`A line-by-line labeling reviewed will be conducted separately.
`
`The Division of Medication Error Prevention and Analysis reviewed the carton and container
`labeling and determined it to be acceptable. See review in DARRTS.
`
`The Division of Medical Policy Programs (DMPP) reviewed the Medication Guide.
`
`13.
`
`Recommendations/Risk Benefit Assessment
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` Recommended Regulatory Action
`
`Approval
`
` Risk Benefit Assessment
`
`The clinical efficacy and safety of the individual components in the proposed fixed
`combination of linagliptin and metformin XR have been established in the Tradjenta and
`Glumetza NDAs, respectively. The efficacy and safety of linagliptin given once daily as add-
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`Cross Discipline Team Leader Review
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`on to metformin given twice daily was demonstrated using adequate and well-controlled Phase
`3 studies in the original NDA for Tradjenta (linagliptin). The efficacy and safety of once daily
`metformin XR was comparable to metformin IR twice daily in the Glumetza NDA. In
`addition, the contribution to glycemic lowering of each of the individual components was
`demonstrated in an adequate and well-controlled factorial study in treatment naïve patients and
`submitted to support approval of Jentadueto for the ‘broad’ indication.
`
`Therefore, the data submitted to support the proposed linagliptin/metformin XR product were
`from relative bioavailability studies designed to bridge the existing clinical efficacy and safety
`data by demonstrating bioequivalence (BE) of each fixed-combination tablet to the co-
`administered free combinations of the individual components.
`
`The pivotal BE studies 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. Hence, the overall data submitted with this NDA support approval.
`
` Recommendation for Postmarketing Risk Evaluation and Management Strategies
`
`None
`
`None
`
` Recommendation for other Postmarketing Requirements and Commitments
`
` Recommended Comments to Applicant
`
`Labeling comments will be communicated to the applicant separately.
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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/
`----------------------------------------------------
`
`LISA B YANOFF
`05/26/2016
`
`JEAN-MARC P GUETTIER
`05/27/2016
`I concur. Dr. Yanoff's review serves as the Divisional Summary memo for this application.
`Efficacy and safety of linagliptin and metformin co-administration was established with data from
`new drug applications 201280 and 201281. The product in this application combines linagliptin
`with the extended release version of metformin and has met the requirements under 21 CFR
`300.50. There are no issues that preclude approval.
`
`Reference ID: 3937675
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`