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

`

`CLINICAL PHARMACOLOGY REVIEW
`
`
`NDA
`Link to EDR
`Submission Date(s)
`Submission Type
`Brand Name
`Generic Name
`
`Dosage Form and Strength
`
`Route of Administration
`Proposed Indication
`
`Applicant
`Associated INDs
`OCP Review Team
`
`208026
`\\CDSESUB1\evsprod\NDA208026\0000
`July 27, 2015
`505(b)(1)
`JENTADUETO XR
`Linagliptin and metformin HCl extended-release fixed dose
`combination tablets
`Tablets; 2.5 mg linagliptin/1000 mg metformin; 5 mg
`linagliptin/1000 mg metformin
`Oral
`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
`Boehringer Ingelheim
`
`Sang M. Chung, Ph.D., Manoj Khurana, Ph.D.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3923497
`
`
`
`Page 1 of 23
`
`(b) (4)
`
`

`

`TABLE OF CONTENTS
`
`
`CLINICAL PHARMACOLOGY REVIEW ............................................................................................ 1 
`1 
`Executive Summary ......................................................................................................................... 3 
`1.1 
`Recommendation.............................................................................................................. 3 
`1.2 
`Post-Market Requirements and Commitments ................................................................ 3 
`Summary of Clinical Pharmacology Assessment ............................................................................ 3 
`2.1 
`Pharmacology and Clinical Pharmacokinetics ................................................................. 3 
`2.2 
`Summary of Labeling Recommendations ........................................................................ 5 
`Comprehensive Clinical Pharmacology Review .............................................................................. 5 
`3.1 
`Overview of the Product and Regulatory Background .................................................... 5 
`3.2 
`Clinical Pharmacology Review Questions ....................................................................... 8 
`3.2.1 
`Does the available clinical pharmacology information provide the pivotal bridging?
` ................................................................................................................................ 8 
`Appendices ..................................................................................................................................... 13 
`4.1 
`Components and composition of JENTADUETO XR ................................................ 13 
`4.2 
`Synopsis: Study 1288.9 .................................................................................................. 14 
`4.3 
`Synopsis: Study 1288.11 ................................................................................................ 19 
`
`2 
`
`3 
`
`4 
`
`
`
`List of Tables
`Table 1 Overview of pivotal bridging studies for linagliptin/metformin FDC XR .................................. 4 
`Table 2 Statistical evaluations for bioequivalence in: least square geometric mean ratios (FDC/co-
`administration) (90% CI) ............................................................................................................. 4 
`Table 3 Currently available FDC products between a DPP-4 inhibitor and metformin, and the pivotal
`bridging information with labeling related to meal conditions for administration (yellow
`highlight indicates a FDC XR) .................................................................................................... 7 
`Table 4 Currently available metformin XR products and the pivotal bridging information with labeling
`related to meal conditions for administration .............................................................................. 7 
`Table 5 Descriptive statistics of PK parameters in Study 1288.9 ........................................................... 10 
`Table 6 Descriptive statistics of PK parameters in Study 1288.11 ......................................................... 12 
`Table 7 accuracy and precision data of quality control samples ............................................................ 12 
`
`List of Figures
`Figure 1 Schematic of the tablet and photographs of JENTADUETO XR ............................................ 6 
`Figure 2 Schematic summary of pivotal bridging information supporting JENTADUETO XR ........... 8 
`Figure 3 Mean (SE) linagliptin (left) or metformin (right) concentration – time profiles by treatments . 9 
`Figure 4 Mean (SE) linagliptin (left) or metformin (right) concentration – time profiles by treatments 11 
`
`
`
`
`
`
`Reference ID: 3923497
`
`
`
`Page 2 of 23
`
`

`

`1 Executive Summary
`
`The applicant has submitted NDA 208026 for JENTADUETO XR, the fixed dose combination
`(FDC XR) of linagliptin and metformin extended-release, as a 505(b)(1) based on the
`bioequivalence (BE) of FDC XR to co-administration of linagliptin and metformin hydrochloride
`(HCl) extended-release in healthy volunteers. 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.
`
`The applicant is the sponsor of linagliptin (TRADJENTA, NDA 201280) and JENTADUETO
`(FDC of linagliptin and metformin HCl twice daily, NDA 201281), and provides a Letter of
`Authorization from the sponsor of metformin extended-release product (GLUMETZA, NDA
`021748).
`
`The applicant refers pertinent labeling information of GLUMETA and JENTADUETO for
`JENTADUETO XR. The following proposed starting dose is acceptable referring those of
`GLUMETA and JENTADUETO:
`
`In patients currently not treated with metformin, initiate treatment with 5 mg linagliptin/1000
`mg metformin hydrochloride extended-release once daily (refer 2.5 mg linagliptin/500 mg
`metformin twice daily as initial treatment for JENTADUETO)
`In patients already treated with metformin, the recommended total daily starting dose 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
`
`
`
`
`
`
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology has reviewed NDA 208026 for JENTADUETO XR and
`recommends approval.
`
`
`
`
`1.2 Post-Market Requirements and Commitments
`
`None
`
`2 Summary of Clinical Pharmacology Assessment
`
`2.1 Pharmacology and Clinical Pharmacokinetics
`
`The efficacy and safety of linagliptin given once daily as add-on to metformin given twice daily
`was adequately demonstrated using Phase 3 study results in the original NDA for
`TRADJENTA (linagliptin). In addition, the efficacy and safety of FDC (linagliptin/metformin)
`
`
`
`Reference ID: 3923497
`
`

`

`was shown with Phase 3 study results of the original NDA for JENTADUETO® including those
`of initial combination therapy with linagliptin and metformin based on results of factorial design
`study, which included efficacy/safety evaluation of the 2.5 mg linagliptin/500 mg metformin IR
`twice daily treatment and unique to JENTADUETOQ development program (refer details to the
`Clinical Pharmacology Review for JENTADUETO® by Dr. Khurana dated 10/11/2011).
`
`The applicant used BE study results as the pivotal supporting information for JENTADUETO®
`XR referencing co—administration of TRADJENTAQ and GLUIvIETZA®. The BB approach has
`been part of other FDC XR development in the same class (DPP-4 inhibitors and metformin
`extended-release formulations such as KOMBIGLYZE® XR and JANUMET9 XR). Basis of the
`BE approach for FDC XR development is that the efficacy and safety of co—administration
`following twice daily dosing is available, and reference product of metformin XR has adequate
`clinical bridging (i.e., efficacy and safety) between once daily and twice daily dosing of
`metformin. Refer specific cases with additional details to section 3.1 of this review.
`
`The applicant conducted two pivotal BE studies because there are two proposed strengths for
`JENTADUETOQ XR under fasted or fed conditions (Table 1).
`
`Table 1 Overview of pivotal bridging studies for linagliptinlrnetfor'min FDC XR
`
`Study No.
`Report No.
`
`Objective and
`description
`
`Study part,
`meal status
`
`Test (FDC dose tested
`(mg))
`
`
`
`Bioequiv.alence-2889-02895304 single—dose
`
`
`
`1288 11
`C027287l4
`
`BioequiValence.
`single—dose
`
`Lina 5 + 4x met XR 500
`
`Reference
`(co—administration dose
`tested m_
`
`
`
`Lina 5 + 2x met XR 500Lina 5 + 2x met XR 500
`
`Lina 5 + 4x met XR 500
`
`
`
`Lina 5/met XR 1000Lina 5/met XR 1000
`
`2x .. 2 5/met XR 1000
`2x lina 2.5/met KR 1000
`
`The BB was demonstrated for both strengths of JENTADUETO® XR referencing corresponding
`co—administration of TRADJENTA® and GLUMETZAQ under both fasted and fed conations
`
`(Table 2).
`
`Table 2 Statistical evaluations for bioequivalence in: least square geometric mean ratios (FDC/co-
`administration) (90% CI)
`
`Stud 1288.9 dose level investi ated: 5/1000 m
`Part 1 (fasted conditions)
`Part 2 (fed conditions)
`
`Linagliptiu
`
`AUCMZ
`
`Cm
`
`Metformin
`
`AUCMZ
`
`Cm
`
`100.4 (96.6. 104.3)%
`
`108.1 (99.0. 118.0)%
`
`100.0 (93.0. 107.5)%
`
`99.8 (92.5. 107.6)%
`
`94.7 (88.7. 101.1)%
`
`98.2 (94.1. 102.6)%
`
`97.0 (92.2. 101.9)%
`
`99.0 (95.0. 103.2)%
`
`Reference ID: 3923497
`
`

`

`
`Study 1288.11 (dose level investigated: 5/2000 mg)
`Part 1 (fasted conditions)
`Part 2 (fed conditions)
`
`
`Linagliptin
`
`AUCtL72
`
`Cm
`
`Metformin
`
`AUC(L72
`
`Cm
`
`103.7 (100.7, 106.7)%
`
`101.6 (93.7, 110.2)%
`
`114.6 (107.7, 121.9)%
`
`98.3 (86.5, 111.6)%
`
`96.5 (91.2, 102.0)%
`
`97.8 (90.5, 105.6)%
`
`98.0 (92.0. 104.3)%
`
`105.9 (96.7, 115.9)%
`
`the clinical pharmacology information of JENTADUETO® XR supports the
`In conclusion,
`recommendation of approval as follows:
`0 The pivotal BE study results are acceptable from the clinical pharmacology perspective
`0 The clinical comparability between metformin twice daily (GLUCOPHAGE®) and once
`daily (GLUMETZA®) was shown in the original NDA for GLUMETZAG, the metformin XR
`reference product for JENTADUETOQ XR
`o The efficacy and safety of co—administration between linagliptin and metformin twice daily
`(GLUCOPHAGEQ) has been adequately demonstrated as add-on (TRADJENTAO) and
`initial (JENTADUETOQ) therapy
`
`2.2 Summary of Labeling Recommendations
`
`To be updated
`
`3 Comprehensive Clinical Pharmacology Review
`
`3.1 Overview of the Product and Regulatory Background
`
`The JENTADUETO® XR consists of a metformin HCl extended release tablet core that is flhn
`
`coated with immediate—release linagliptin figure 1). Components and composition of
`formulations are summarized in Appendix.
`
`Reference ID: 3923497
`
`

`

`Figure 1 Schematic of the tablet and photographs of JENTADUETO XR
`
`
`General regulatory background
`
` A
`
` typical clinical development for a FDC product of a DPP-4 inhibitor and metformin is based
`on the pivotal BE bridging of a FDC referencing co-administration of each products of active
`ingredients, and efficacy and safety of a DPP-4 inhibitor for add-on to metformin BID, which is
`typically available from the original NDA for a DPP-4 inhibitor (Table 2). Meal conditions for a
`FDC administration is followed by those of metformin reference product as the meal condition
`for a DPP-4 inhibitor is generally not limited (Table 2).
`
`For FDC XR development, the pivotal BE bridging of a FDC XR referencing co-administration
`of a DPP-4 inhibitor and metformin XR, and efficacy and safety of co-administration of a DPP-4
`inhibitor and metformin BID with clinical comparability between once daily and twice daily of
`metformin from metformin XR reference product. Currently three approved metformin XR
`products are available with different extended-release mechanisms and clinical bridging
`information (Table 3).
`
`
`Product specific regulatory background
`
`The efficacy and safety of linagliptin 5 mg once daily for add-on to a stable metformin twice
`daily with GLUCOPHAGE was shown in the original NDA for TRADJENTA (NDA
`201280). Further, in the original NDA for JENTADUETO (NDA 201281) the efficacy and
`safety as the initial therapy following co-administration of linagliptin and metformin
`(GLUCOPHAGE) twice daily was shown and the pivotal BE of FDC referencing co-
`administration of TRADJENTA and GLUCOPHAGE was demonstrated. The efficacy and
`safety of GLUMETZA(metformin XR) once daily was comparable to that of GLUCOPHAGE
`(metformin IR) twice daily with in the original NDA for GLUMETZA (NDA 021748).
`
`The BE of JENTADUETO XR was demonstrated referencing co-administration of
`TRADJENTA and GLUMETZA. Therefore, there is sufficient bridging information for
`JENTADUETO XR to refer pertinent labeling from TRADJENTA, GLUMETZA and
`JENTADUETO (Figure 2).
`
`
`
`
`Reference ID: 3923497
`
`(b) (4)
`
`

`

`BE+ foodefi'ect (5/500 underfastor low 5.1,
`5+500)
`BE (5/1000 under low fat)
`. BE (so/500, 100/1000; 25150/500, 50+500,
`100+1000) unda' high fat breakfast
`. Food erred study (50/1000, JANUMET"
`(so/1000))
`. BE (50/500, 50/850; 50/1000 FM] vs.
`JANUVIA° + GLUCOPAHGE' EU) under
`
`0 Food efim
`
`
`Approximately the same as of
`GLUCOPAHGEo (two Phase 3
`studies)
`
`1mm“ Willi 500 mg daily “0'5 exceeding “It
`maximum recommend daily dose of2000 mg
`with the evening meal
`
`Table 3 Currently available FDC products between a DPP—4 inhibitor and metformin, and the pivotal
`bridging information with labeling related to meal conditions for administration (yellow highlight
`indicates a FDC XR)
`
`Combination
`Productsl
`JANUME'I‘O
`(sitagliptin/
`f
`.
`IR)
`AP: 3/30/2007
`
`Referencing
`products
`
`'
`
`'
`
`'
`
`.
`
`KOMBFQL‘IQE. XR
`(“Mm
`“mm“
`)
`11/5/2010
`
`0NGLYZA°
`(saxaglitpin) +
`GLUCOPAHGE’ 1m
`
`.
`
`,
`
`,
`
`,
`
`Major bridging information
`
`.
`_
`_
`BE under fasting conditions
`
`JANUME'I‘ 2m“
`(sitagliptin/
`metformin XR)
`AP: 2/2/2012
`
`o
`
`JENTADUEI‘O
`“WW““I’R
`“mm )
`AP: 1/30/2012
`KAZANO‘
`(alogliptinl
`metfimin IR)
`AP: 1/25/2013
`
`JANUVIA'
`(sitagliptin) +
`GLUMETZA°
`
`'
`
`‘
`
`'
`
`2.5/500’
`2.5/850,
`2.5/1000
`
`11.251101o (alogliptin)
`+GLUCOPHAGE°
`
`12.5/500,
`12.5/1000
`
`BEnnderfiistingcondition
`
`0 BE under fasting condition
`
`chronological order by Approval (AP) date
`
`Table 4 Currently available metformin XR products and the pivotal bridging information with labeling
`related to meal conditions for administration
`
`Referencing
`
`Major bridging
`
`D&A (starting and maximum dose,
`1... .............=
`
`GLUCOPAHGEo XR
`AP: 10/13/2000
`
`GLUCOPAHGE'
`
`500 750
`,
`
`FORTAMET”
`AP: 4/28/2004
`
`GLUCOPAHGEo
`
`500, 1000
`
`3
`
`(twoPl
`-R
`D
`-
`-
`studies With 12—16 weeks)
`.
`.
`5mm efficacy to
`GLUCOPAHGE" (24 weeks)
`Close efficacy to
`GLUCOPAHGEo (three Phase 3
`studies)
`
`500mgoncedailywiththeeveningmeal
`Dosageincreases should be madein
`ementsofSOOmgweekly,uptoa
`in“
`”mm°f200° "'3 °“‘° “any ““1 “1°
`Stan 1000 mg although 500 may be utilized,
`the maximum recommend daily dose up to
`2500 mg with the evening meal
`
`GLUCOPAHGEo
`
`500, 1000
`
`GLUl [ETZ I .4
`AP- 6/3/2005
`'
`Chronological order by Approval (AP) date
`2 Dosage and administration
`3It is fimnnlated using the patented single—composition o-ntic technology
`‘Itis fmnmlatedtogladuaflyreleasemed'omnntotheuppergasn'ommmnad
`
`Reference ID: 3923497
`
`

`

`0
`JENTADUETO XR
`
`TRADJENTA
`(Linagliptin)
`
`BE: FDC vs. co—administration
`
`o
`
`' (2 x 2.5/1000) vs. (Lina 5 + 4x500 (GLUMETZA ))
`o
`
`' (5/1000) vs. (Lina 5 + 2x500 (GLUMETZA )
`
`
`
`(FDC: Lina/Met XR)
`
`
`E/S of linagliptin CD + metformin BID
`
`O
`(GLUCOPHAGE )
`
`I E/S of (linagliptin + metformin) BID
`E BE: FDC vs. co-administration
`:I
`
`G
`
`JENTADUETO
`
`(FDC: Lina/Met IR)
`
`Figure 2 Schematic summary of pivotal bridging information supporting JENTADUETO' XR
`
`3.2 Clinical Pharmacology Review Questions
`
`3.2.1 Does the available clinical pharmacology information provide the pivotal bridging?
`
`Yes, because the BE of JENTADUETO® XR was demonstrated referencing co-administration of
`TRADJENTA® and GLUMETZA® in two different dose levels (i.e., 5 mg linagliptin/1000 mg
`metformin XR and 5 mg linagliptin/2000 mg metformin XR)
`
`The BB of linagliptin and metformin following JENTADUETO® XR (one tablet of 5/1000) was
`assessed referencing those of co—administration of TRADJENTA® (one tablet 5 mg) and
`GLUMETZA® (two tablets 500 mg) under fasted and fed (high-fat) conditions in a two-way
`crossover trial with healthy volunteers (Study 1288.0009).
`
`Plasma concentration of linagliptin and metformin — time profiles by treatments are shown in
`Figure 3 and pharmacokinetic parameters are summarized in Table 5. The FDC of 5 mg
`linagliptin/1000 mg metformin XR is bioequivalent to co-administration of single tablet 5 mg
`linagliptin and 1000 mg metformin XR (two tablets 500 mg) both under fasted and fed
`conditions (Table 2).
`
`Reference ID: 3923497
`
`

`

`STUDY 9: 5/1000 vs. 5+1000
`
`Linagliptin
`
`(nmoVL)
`
`0
`
`8
`
`16
`
`24
`
`32
`
`40
`
`48
`
`56
`
`64
`
`72
`
`TRT
`
`O FAST:5+I000 + FAST:5/|000 X FED: 5+1000 A FED:5/l000
`
`Time (Hour)
`
`
`
`
`
`
`
`STUDY 9: 5/1000 vs. 5+]000
`
`Metformin
`
`(ng/mL)
`
`Time (Hour)
`
`TRT O FASHSHOOO + FASTz5/IOOO >< FED:5+1000 A FED: 5/1000
`
`
`Figure 3 Mean (SE) linagliptin (left) or metformin (right) concentration — time profiles by treatments
`
`Reference ID: 3923497
`
`

`

`
`
`Part 2 (fed conditions)
`FDC Co-
`administration
`14 15
`226 (41.2%) 252 (23.7%)
`5.76 (49.6%) 6.30 (23.4%)
`392 (59.8%) 419 (33.5%)
`2.00 (0.333, 24.0) 2.00 (0.683, 5.00)
`55.7 (44.9%) 52.7 (30.3%)
`14 15
`11000 (167%) 14800 (23.2%)
`928 (183%) 1260 (26.7%)
`15 200 (22.7%)1 15 100 (23.5%)
`6.00 (5.00, 12.0) 6.00 (5.00, 8.00)
`48.0 (24.0, 72.0) 48.0 (48.0, 72.0)
`12.8 (116%)1 13.0 (80.0%)
`
`Table 5 Descriptive statistics of PK parameters in Study 1288.9
`Part 1 (fasted conditions)
`FDC Co-
`administration
`Linagliptin, N analyzed 52 52
`AUC0-72, gMean (gCV) [nmol·h/L] 288 (24.1%) 287 (23.9%)
`Cmax, gMean (gCV) [nmol/L] 9.54 (36.1%) 8.83 (28.1%)
`AUC0-∞, gMean (gCV) [nmol·h/L] 460 (31.9%) 461 (27.8%)
`tmax, median (min, max) [h] 3.00 (0.333, 6.05) 4.00 (0.667, 6.02)
`t1/2, gMean (gCV) [h] 52.5 (24.1%) 53.1 (21.8%)
`Metformin, N analyzed 52 52
`AUC0-tz, gMean (gCV) [ng·h/mL] 7150 (26.7%) 7150 (31.9%)
`Cmax, gMean (gCV) [ng/mL] 924 (31.0%) 926 (30.9%)
`AUC0-∞, gMean (gCV) [ng·h/mL] 7540 (28.7%) 7610 (32.4%)
`tmax, median (min, max) [h] 4.00 (3.00, 6.00) 4.00 (2.00, 6.02)
`tz, median (min, max) [h] 48.0 (24.0, 72.0) 48.0 (24.0, 72.0)
`t1/2, gMean (gCV) [h] 13.5 (108%) 15.1 (109%)
` gCV: geometric coefficient of variation between subjects
` 1 N analyzed=13
`
`The bioequivalence of linagliptin and metformin following JENTADUETO XR (two tablets of
`2.5/1000) was assessed referencing those of co-administration of TRADJENTA (one tablet 5
`mg) and GLUMETZA (four tablets 500 mg) under fasted and fed (high-fat) conditions in a two-
`way crossover trial with healthy volunteers (Study 1288.0011).
`
`Plasma concentration of linagliptin and metformin – time profiles by treatments are shown in
`Figure 4 and pharmacokinetic parameters are summarized in Table 6. The FDC at dose level of 5
`mg linagliptin/2000 mg metformin XR is bioequivalent to co-administration of 5 mg linagliptin
`(single tablet 5 mg) and 2000 mg metformin XR (four tablets 500 mg) both under fasted and fed
`conditions (Table 2).
`
`
`
`
`
`
`Reference ID: 3923497
`
`

`

`STUDY 11: 2*2.5/1000 vs. 5+4*500
`
`0
`
`8
`
`16
`
`24
`
`TRT
`
`FAST: 2*2.5/1000
`
`40
`32
`Time (Hour)
`FAST: 5+4*500
`
`48
`
`56
`
`64
`
`72
`
`FED: 2*2.5/1000
`
`FED: 5+4*500
`
`STUDY 11: 2*2.5/1000 vs. 5+4*500
`
`10
`
`1
`
`0.1
`
`1000
`
`100
`
`10
`
`0
`
`8
`
`16
`
`24
`
`TRT
`
`FAST: 2*2.5/1000
`
`40
`32
`Time (Hour)
`FAST: 5+4*500
`
`48
`
`56
`
`64
`
`72
`
`FED: 2*2.5/1000
`
`FED: 5+4*500
`
`Figure 4 Mean (SE) linagliptin (left) or metformin (right) concentration – time profiles by treatments
`
`
`
`
`Reference ID: 3923497
`
`
`
`
`
`

`

`
`Table 6 Descriptive statistics of PK parameters in Study 1288.11
`
`
`
`
`
`
`Part 2 (fed conditions)
`FDC Free
`combination
`15 16
`270 (18.5%) 265 (14.1%)
`6.61 (28.7%) 6.73 (19.9%)
`452 (22.1%) 446 (16.5%)
`2.00 (0.333, 5.03) 3.51 (0.667, 5.00)
`54.1 (23.7%) 55.9 (19.5%)
`15 15
`19 800 (16.3%) 20 300 (17.1%)
`1650 (21.0%) 1570 (12.9%)
`20 200 (16.7%) 20 600 (17.8%)
`6.00 (5.00, 8.00) 5.00 (4.00, 6.00)
`72.0 (48.0, 72.1) 72.0 (48.0, 72.0)
`13.1 (71.8%) 12.3 (63.3%)
`
`Part 1 (fasted conditions)
`FDC Free
`combination
`Linagliptin, N analyzed 57 55
`AUC0-72, gMean (gCV) [nmol·h/L] 289 (22.4%) 279 (23.4%)
`Cmax, gMean (gCV) [nmol/L] 9.49 (36.2%) 8.19 (28.2%)
`AUC0-∞, gMean (gCV) [nmol·h/L] 475 (29.4%) 458 (30.6%)
`tmax, median (min, max) [h] 3.00 (0.333, 6.02) 4.00 (0.667, 12.0)
`t1/2, gMean (gCV) [h] 55.8 (25.0%) 54.7 (24.8%)
`Metformin, N analyzed 56 56
`AUC0-tz, gMean (gCV) [ng·h/mL] 11 600 (35.9%) 12 000 (31.9%)
`Cmax, gMean (gCV) [ng/mL] 1490 (33.2%)1 1520 (33.1%)
`AUC0-∞, gMean (gCV) [ng·h/mL] 12 100 (37.3%) 12 700 (33.9%)
`tmax, median (min, max) [h] 4.00 (2.00, 5.03) 1 3.51 (1.50, 5.02)
`tz, median (min, max) [h] 48.0 (12.0, 72.1) 48.0 (34.0, 72.1)
`t1/2, gMean (gCV) [h] 13.7 (93.1%) 14.8 (88.3%)
` gCV: geometric coefficient of variation between subjects
` 1 N analyzed=57
`
`GLUMETZA labeling indicates that high-fat and low fat meals increase metformin AUC by
`73% and 38%, respectively, compared to those of fasting. It seems that high-fat meal increase
`similar metformin AUC from JENTADUETO XR, and it further support that JENTADUETO
`XR can refer the same labeling for meal condition related to dosing administration as that of
`GLUMETZA.
`
`Plasma concentrations of linagliptin and metformin were measured using validated HPLC-
`MS/MS methods. Accuracy and precision data of quality control samples are shown in Table 7.
`The Office of Study Integrity and Surveillance recommends that the bioanalytical data be
`accepted for review (refer details to the review by Dr. Li-Hong Paul Yeh dated 3/15/2016).
`
`Table 7 accuracy and precision data of quality control samples
`
`
`
`Reference ID: 3923497
`
`
`
`

`

`4 Appendices
`
`4.1 Components and composition of JENTADUETOO XR
`
`5 mg! 1000 mg
`2.5 mg/ 1000 mg
`mm.“ W...“
`
`Reference to
`mm.
`
`
`
`Reference ID: 3923497
`
`

`

`4.2 Synopsis: Study 1288.9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3923497
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Diagnosis:
`
`
`
`
`Not applicable
`
`
`
`
`
`
`Main Criteria for
`
`Inclusion:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Healthy male and female subjects. age 18 to 55 yeais. body mass index
`
`
`
`
`
`(BMI) 18.5 to 29.9 kg/in2
`
`
`
`
`
`BI lm’estigational Product:
`
`
`
`
`
`
`
`
`
`
`
`
`
`5 mg linagliptits’lOOO mg metformin XR FDC tablet
`
`Dose:
`
`
`
`
`
`
`
`
`
`
`
`
`
`5 mg liuagliptinflOOO mg metformin XR (given as l FDC tablet)
`
`
`
`
`
`Mode of Admin:
`
`
`
`Batch No;
`
`
`
`
`
`Comparator Products:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Oral with 240 mL of water after an overnight fast of at least 10 h for the
`
`
`
`
`
`
`
`
`
`
`
`
`fasted study part and after a high-fat. high-calorie meal for the fed study pan
`3141000803
`
`
`
`
`
`
`
`
`
`
`
`
`Comparator product 1: ”I‘radjentaa (5 mg ljnagliptin tablet)
`
`
`
`
`
`
`
`
`
`Comparator product 2: Glumetzag (500 mg inetforinin KR tablet)
`
`Dose:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg
`
`
`
`
`
`
`
`
`linagliptin and 2 tablets 500 mg metfonnin KR)
`
`
`
`
`
`Mode of Admin.:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Oral with 240 2131.. of water after an overnight fast of at least 10 h for the
`
`
`
`
`
`
`
`
`
`
`
`
`fasted study part and after a high-fat. high-calorie meal for the fed study part
`
`
`
`
`
`
`Batch No;
`
`
`
`
`
`
`Duration of Treatment:
`Criteria for Evaluation:
`
`
`
`
`
`
`Clinical
`
`Pharmacology:
`
`
`
`
`
`
`
`Tradjentag 5 mg: 3141000802
`
`
`
`
`(CilunietzaE 500 mg: BHIOOOSOI
`
`
`
`
`
`
`
`
`
`Single dose for each treatment
`
`
`
`
`
`
`
`
`
`
`
`The following pharmacokinetic parameters were evaluated as primary
`
`
`
`
`
`
`
`
`endpoints: AUCME and Cm for linagliptin. AUCCHZ and Cm for metformin
`
`
`
`
`
`
`
`
`
`
`The following pharmacokinetic parameters were evaluated as secondary
`
`
`
`
`
`
`endpoints: AUC‘OJ for both linagliptin and nietformin
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The evaluation of safety was based 011: adverse events (including clinically
`
`
`
`
`
`
`
`
`
`
`relevant fuidings from the physical examination). safety laboratory tests. vital
`
`
`
`
`
`
`
`
`signs (blood pressure. pulse rate). ll-lead electrocardiogram (ECG)
`
`
`Reference ID: 3923497
`Reference ID: 3923497
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Geometric mean (gMean) plasma concentration-tune profiles and
`
`
`
`
`
`
`
`
`
`
`phaimacokinetic parameters of linagliptin and metformin were similar for the
`
`
`
`
`
`
`
`
`
`
`
`
`
`FDC and the free combination in each study part. The adjusted gMean values.
`
`
`
`
`
`
`
`
`
`
`
`
`the adjusted gMean ratios (FDC to free combination). 2-sided 90% CIs. and
`
`
`
`
`
`
`
`
`
`intra-subject geometric coefficient of variation (gCV) values for all primary
`
`
`
`
`
`
`
`
`
`and secondary endpoints are summarised in Table 1 below.
`
`
`
`
`
`Statistical Methods:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The assessment of bioequivaience was based upon 2-sided 90% confidence
`
`
`
`
`
`
`
`
`
`
`
`intervals (C'Is) for the ratios of the geometric means (FDCi’free combination)
`
`
`
`
`
`
`
`
`
`
`
`
`for the primary endpoints using an acceptance range of 80.00 to 125.00%.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`This method is equivalent to the two l—sided t-tests procedure. each at the 5%
`
`
`
`
`
`
`
`
`
`significance level. The statistical model was an analysis of variance
`
`
`
`
`
`
`
`
`
`
`(ANOV’A) on the logarithmic scale including effects for ‘sequence‘. ‘subjects
`
`
`
`
`
`
`
`
`
`
`within sequences’. period. and ‘treatinent‘. CIs were calculated based on the
`
`
`
`
`
`
`
`
`
`
`
`residual error from ANOVA. Descriptive statistics were calculated for all
`
`
`
`
`
`
`endpoints. No interim analysis was performed.
`
`
`
`
`SL'lVli‘IARY — CONCLUSIONS:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A total of 68 healthy volunteers participated in the study.
`
`
`
`
`
`
`
`
`
`
`
`
`Fifty-two subjects participated in Part 1. all of whom completed the study as
`
`
`
`
`
`
`
`
`
`
`planned. Twenty-three study participants were male (44.2%) and 29 were
`
`
`
`
`
`
`
`
`
`
`
`
`female (55.8%). Age ranged from 19 to 54 years (mean: 34.7 years. standard
`
`
`
`
`
`
`
`
`
`
`
`
`deviation [51D]: 10.4 years). ‘and BMI ranged from 19.! to 29.1 lcgr’m2 (mean:
`
`
`
`23.93 kgi’m’. SD: 2.47 kgfm‘).
`
`
`
`
`
`
`
`
`
`
`
`
`Sixteen subjects participated in Part 2. three of whom prematurely
`
`
`
`
`
`
`
`
`
`discontinued study participation. Two subjects discontinued due to adverse
`
`
`
`
`
`
`
`
`
`
`
`
`events: 1 subject after having been treated with the free combination and
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 subject after having been treated with the FDC‘ in the first treatment period.
`
`
`
`
`
`
`
`
`
`
`
`One subject withdrew consent after having been treated with the free
`
`
`
`
`
`
`
`
`
`
`
`combination. Six study participants were male (37.5943) and 10 were female
`(625%). Age ranged from 18 to 53 years (mean: 36.1 years. SD: 1 1.9 years).
`
`
`
`
`
`and BMI ranged from 19.6 to 29.1 ltg/ml (mean: 24.54 kgKniz. SD:
`
`
`
`
`2.96 kg’nfi).
`
`
`
`
`
`
`
`
`
`
`
`
`
`All 63 subjects in this study were White. No relevant medical history or
`
`
`
`
`
`
`
`
`
`
`
`baseline conditions were reported for any of the participating subjects. All
`
`
`
`
`
`
`
`
`
`
`
`
`subjects were treated with at least 1 dose of study medication. No important
`
`
`
`
`protocol violations were reported.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Trial Subjects and
`
`
`Compliance with
`Trial Protocol:
`
`
`
`
`
`Clinical
`
`
`Pharmacology
`Results:
`
`
`
`
`
`
`
`
`Reference ID: 3923497
`Reference ID: 3923497
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`For each study part. the adjusted gMean ratios FDC‘ to free combination for
`
`
`
`
`
`
`
`
`
`
`the mining: endpoints (AUCug; and Cm“ of linagliptin and AUG,42 and Cm;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of metfonnin) were close to 100%. with their corresponding 90% (‘18 within
`
`
`
`
`
`
`
`
`
`
`the pre-defined acceptance range for bioequivalence of 80.00 to 125.00%.
`
`
`
`
`
`
`
`
`
`
`
`The adjusted gMean ratios for the secondary endpoint. AUCM, of linagliptin
`
`
`
`
`
`
`
`
`
`
`
`and metformin. were close to 100%. with their corresponding 90% C‘Is within
`
`
`
`
`
`
`
`
`
`
`the acceptance range for bioequivalence. except for AUG}m of linagliptin
`under fed conditions. for which the lower limit of the 90% CI was outside the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`bioequii'alence limit.
`
`
`
`
`
`
`
`
`Table 1:
`
`
`
`
`
`
`
`
`
`Analysis of bioequivalence of linagtiptin and metformin after
`
`
`
`
`
`
`
`
`
`administration of 5 mg linagliptin and 1000 mg metfonnin XIR
`as FDC or free combination
`
`
`
`
`
`
`Analyte
`
`Parameter
`
`
`Part 1 (fasted conditions)
`
`
`
`
`
`
`Adjusted
`gMean
`
`FDC
`
`
`
`
`
`
`Adjusted
`gMean
`
`fi'ee
`
`combination
`
`
`
`Adjusted
`
`gMean ratio
`FDCI‘free
`
`combination
`[9%]
`
`
`
`
`
`
`
`90% CI
`
`(upper limit.
`
`lower limit)
`
`
`1%]
`
`
`Imm—
`individual
`gCV
`
`[%]
`
`
`
`
`Linagliptin (FDC N=52‘ flee combination N=52)
`
`
`
`
`
`AUG“: [nmol-hfL]
`288
`287
`
`
`
`
`8.83
`Cm[nmolfL]
`9.54
`
`
`
`
`AUCom [mnOl-hf'L]
`460
`461
`
`
`
`Metformin (FDC N=Sl free combination N=5 2)
`
`
`
`
`
`AUQHz [ng-hme]
`7146
`7147
`
`
`
`924
`Cm [ng/mL]
`926
`
`
`
`AUCM [11-11;le
`7540
`7608
`
`
`
`
`Part 2 (fed conditions)
`
`
`
`
`
`
`
`
`
`
`
`100.4
`
`108.1
`
`99.7
`
`
`100.0
`
`99.8
`
`99.1
`
`
`(96.6. 104.3)
`
`
`(99.0. 118.0)
`
`
`(95.2. 104.5)
`
`
`
`(93.0. 107.5)
`
`
`(92.5. 107.6)
`
`
`(92.4, 106.4)
`
`
`
`11.8
`27.1
`14.3
`
`
`
`
`
`22.2
`
`23.4
`
`21.7
`
`
`
`
`
`
`
`
`Linagliptin (FDC N=14. free combination N=15)
`AUCo_-;3[nmol-h/L]
`222
`234
`
`
`
`
`(:m [nmol/L]
`5.79
`5.69
`
`
`
`
`AUCO,” [nmol-b’L]
`387
`398
`
`
`
`Metformin (FDC N=14, free combination N=15)1
`
`
`
`
`
`
`
`
`
`
`
`
`
`7.1
`(92.2. 101.9)
`97.0
`AUCM, [ng-hme]
`10 980
`11 326
`
`5.9
`(95.0. 103.2)
`99.0
`938
`cm [ng/mL]
`947
`
`
`
`
`
`
`
`
`(93.3, 103.3)
`15 047'
`AUC..., 11;an 1
`14 774
`93.2
`7.2
`
`
`
`
`
`
`
`
`' One subject excluded from AUG).n calculation for the fDC (FDC N=13. fi‘ee combination N=15)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`94.7
`98.2
`97.4
`
`
`
`
`
`(88.7, 101.1)
`
`
`(94.1. 102.6)
`
`
`(77.1. 123.0)
`
`
`
`9.2
`6.1
`32.4
`
`
`
`
`
`
`
`
`
`
`
`
`
`Clinical
`
`
`Pharmacology
`
`
`Results (cont):
`
`
`Reference ID: 3923497
`Reference ID: 3923497
`
`

`

`
`
`In Part 2. AB were reported for 5 of 15 subjects (33.3%) during the treatment
`period with the the combination and for 4 of 14 subjects (28.6%) dining the
`treatment period with the FDC‘ tablet. Two subjects were reported with SAEs
`after treatment with the free combination: 1 subject had a fall and 1 subject
`had a road traffic accident. 26 and 15 days after the day of drug intake.
`respectively. The SAEs were severe in intensity: all other AEs were of mild
`or modera