206073Orig1s000 - Food and Drug Administration...Page 1 of 45 Reference ID: 3640237 OFFICE OF CLINICAL PHARMACOLOGY REVIEW. NDA: 206073 Submission Date(s): January 30, 2014 . Brand

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

206073Orig1s000

CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S)

1

BIOPHARMACEUTICS REVIEW ADDENDUMOffice of New Drug Quality Assessment

Application No.: NDA 206-073Reviewer: Kareen Riviere, Ph.D.

Submission Date(s): 1/30/14; 6/3/14

Division: DMEP Secondary Signature: Tapash Ghosh, Ph.D.

Applicant:Boehringer Ingelheim Pharmaceuticals, Inc.

Supervisor: Paul Seo, Ph.D.

Trade Name: Glyxambi Date Assigned:

1/30/14

Generic Name: empagliflozin/linagliptin fixed-dose combination tablets

Date of Review:

10/15/14

Indication: adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Type of Submission: 505(b)(1) New Drug Application

Formulation/strengths: IR Tablet; 10 mg/5 mg and 25 mg/5mg

Route of Administration:

Oral

In the Biopharmaceutics review dated September 16, 2014, Dr. Kareen Riviere stated that Glyxambi (empagliflozin/linagliptin) 10 mg/5 mg and 25 mg/5mg immediate release tablets are recommended for approval from a Biopharmaceutics standpoint pending the OSI inspection results for the pivotal BE Study 1275.3. In the OSI inspection report for Study 1275.3 dated October 3, 2014, Drs. Seongeun (Julia) Cho and Sripal R. Mada stated:

Based on the inspectional outcomes, these reviewers conclude that the clinical and analytical portions of the Study 1275.003 are acceptable for further Agency review.

Thus, NDA 206-073 for Glyxambi (empagliflozin/linagliptin) 10 mg/5 mg and 25 mg/5mg immediate release tablets is recommended for approval from the Biopharmaceutics perspective.

Kareen Riviere, Ph.D. Tapash Ghosh, Ph.D. Biopharmaceutics Reviewer Biopharmaceutics Team Leader Office of New Drug Quality Assessment Office of New Drug Quality Assessment

cc: Dr. Paul Seo

Reference ID: 3643612

---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

KAREEN RIVIERE10/15/2014

TAPASH K GHOSH10/15/2014


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OFFICE OF CLINICAL PHARMACOLOGY REVIEW NDA: 206073

Submission Date(s): January 30, 2014

Brand Name Glyxambi Generic Name Empagliflozin / Linagliptin FDC

OCP Division Clinical Pharmacology -2

OND division Metabolism and Endocrinology Products

Sponsor Boehringer Ingelheim Pharmaceuticals, Inc.

Submission Type; Code

NDA 505(b)(1); Standard

Formulation; Strength(s)

Tablets: • 10 mg empagliflozin/5 mg linagliptin • 25 mg empagliflozin/5 mg linagliptin

Proposed Indication • Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when both empagliflozin and linagliptin is appropriate.

Dosage & Administration

• The recommended starting dose of Glyxambi is 10 mg empagliflozin/5 mg linagliptin once daily.

• Dose can be increased to 25 mg empagliflozin/5 mg linagliptin once daily in patients who require additional glycemic control.

• Glyxambi can be taken with or without food. • Do not initiate Glyxambi if eGFR is below 45

mL/min/1.73 m2 Clinical Pharmacology Reviewer

Suryanarayana Sista, PhD

Clinical Pharmacology Team Leader (Acting)

Manoj Khurana, PhD


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TABLE OF CONTENTS

1 Executive Summary ................................................................................................................ 5 1.1 Recommendation ............................................................................................................. 5 1.2 Phase IV Commitments.................................................................................................... 5 1.3 Summary of Important Clinical Pharmacology Findings ................................................ 5

2 Question-Based Review (QBR) .............................................................................................. 6 2.1 What are the in vivo Clinical Pharmacology and Biopharmaceutics studies with PK

information submitted in the NDA .............................................................................. 6 2.1.1 What are the highlights of the Glyxambi drug product as they relate to clinical

pharmacology review? ............................................................................................ 9 2.1.2 What is the composition of to-be-marketed formulation of Glyxambi? ................. 9 2.1.3 What are the proposed mechanism of action and therapeutic indications? ........... 10 2.1.4 What are the proposed dosages and routes of administration? ............................. 12

2.2 General Clinical Pharmacology ..................................................................................... 12 2.2.1 What is known about the PK characteristics of Empagliflozin and Linagliptin following

the administration of approved drugs, Jardiance and Tradjenta tablets? .............. 12 2.2.2 Were the active moieties in the plasma appropriately identified and measured to assess

the pharmacokinetics? ........................................................................................... 13 2.3 Intrinsic Factors .............................................................................................................. 14

2.3.1 What intrinsic factors (e.g., weight, gender, race, age, height, disease, genetic polymorphism, pregnancy, and organ dysfunction) influence exposure (PK usually) and/or response, and what is the impact of any differences in exposure on efficacy or safety responses?................................................................................................... 14

2.4 Extrinsic Factors ............................................................................................................ 14 2.4.1 What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence

exposure and/or response and what is the impact of any differences in exposure on pharmacodynamics? .............................................................................................. 14

2.5 General Biopharmaceutics ............................................................................................. 14 2.5.1 Was bioequivalence established between Empagliflozin and Linagliptin FDC

formulations and individual components? ............................................................ 14 2.5.2 What is the effect of food on the bioavailability of Empagliflozin and Linagliptin from

the FDC ................................................................................................................. 15 2.5.3 How did the systemic exposure of empagliflozin and linagliptin from FDA compare to

the individual treatment in the Phase III program? ............................................... 21 2.6 Exposure Response ........................................................................................................ 23

2.6.1 Is there an exposure-response (e.g. dose-response, concentration-response) relationship for effectiveness and safety for empagliflozin/linagliptin FDC in T2DM patients?23

2.7 Analytical ....................................................................................................................... 27 2.7.1 Is the analytical method for Empagliflozin and Linagliptin appropriately validated?

.............................................................................................................................. 27 3 Labeling Comments (Preliminary) ....................................................................................... 29 4 APPENDIX ........................................................................................................................... 38

OCP Filing Memo .............................................................................................................................. 38 General Information About the Submission ........................................................................... 39


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List of Tables Table 1: Overview of studies with pharmacokinetic assessments relevant to the clinical

pharmacology and biopharmaceutics of Glyxambi ......................................................... 7 Table 2 Qualitative and quantitative composition of empagliflozin / linagliptin film-coated

tablets ............................................................................................................................... 9 Table 3: Summary Statistics for Empagliflozin Pharmacokinetic Parameters following

administration of FDC formulation consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions to healthy subjects .................................... 16

Table 4: Bioequivalence and Food Effect Comparisons for Empagliflozin following administration of FDC formulation consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions in healthy subjects .................................... 16

Table 5: Summary Statistics for Linagliptin Pharmacokinetic Parameters following administration of FDC formulation consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions to healthy subjects .................................... 19

Table 6: Bioequivalence and Food Effect Comparisons for Linagliptin following administration of FDC formulation consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions in healthy subjects ............................................................... 19

Table 7: Empagliflozin plasma trough concentrations (geometric mean, CV) in patients who were on metformin background therapy and treatment naïve patients from Study 1275.1 ....................................................................................................................................... 22

Table 8: Linagliptin plasma trough concentrations (geometric mean, CV) in patients who were on metformin background therapy and treatment naïve patients from Study 1275.1 .... 22

Table 9: HbA1c (%) change from baseline MMRM results at week 24 − FAS(OC) (add-on therapy to metformin background) ................................................................................ 24

Table 10: HbA1c (%) change from baseline MMRM results at week 52 − FAS(OC) (add-on therapy to metformin background) ................................................................................ 24

Table 11: HbA1c (%) change from baseline MMRM results at week 24 – FAS (OC) (treatment naïve) ............................................................................................................................. 26

Table 12: HbA1c (%) change from baseline MMRM results at week 52 – FAS (OC) (treatment naïve) ............................................................................................................................. 26

Table 13 Summary of key descriptive parameters for Empagliflozin and Linagliptin bioanalytical assays used in clinical studies ........................................................................................ 28


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List of Figures

Figure 1: Food-effect Comparison for Empagliflozin and linagliptin following 25 mg Empagliflozin/5 mg Linagliptin FDC Formulation under Fasting and Fed Conditions .. 6

Figure 2: Empagliflozin mechanism of action .............................................................................. 11 Figure 3: Linagliptin mechanism of action ................................................................................... 11 Figure 4: Mean plasma concentration time profile of empagliflozin following FDC formulation

consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions ....................................................................................................................................... 15

Figure 5: Boxplot of Cmax vs. Treatment for Empagliflozin .......................................................... 17 Figure 6: Boxplot of AUC0-t vs. Treatment for Empagliflozin ...................................................... 17 Figure 7: Boxplot of AUC0-∞ vs. Treatment for Empagliflozin .................................................... 18 Figure 8: Mean plasma concentration time profile of linagliptin following FDC formulation

consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions ....................................................................................................................................... 18

Figure 9: Boxplot of Cmax vs. Treatment for Linagliptin ............................................................... 20 Figure 10: Boxplot of AUC0-t vs. Treatment for Linagliptin ........................................................... 20 Figure 11: Boxplot of AUC0-∞ vs. Treatment for Linagliptin.......................................................... 21 Figure 12: Adjusted mean change in HbA1c (%) over time from baseline based on mixed-model

repeated measures (MMRM) of the full analysis dataset (FAS) observed case (OC) (add-on therapy to metformin background) ................................................................... 23

Figure 13: Adjusted mean change in HbA1c (%) over time from baseline based on mixed-model repeated measures (MMRM) of the full analysis dataset (FAS) observed case (OC) (treatment naïve) ............................................................................................................ 25


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1 Executive Summary Boehringer Ingelheim Pharmaceuticals, Incorporated Inc. (BI) is seeking US marketing approval for Glyxambi tablets under the provisions of Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act. Glyxambi is a fixed-dose combination (FDC) product of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Empagliflozin (Jardiance, NDA 204629, BI) and linagliptin (Tradjenta, NDA 201280, BI) were approved by the Agency on 08/01/2014 and 05/02/2011, respectively. The proposed indication of Glyxambi tablets is “adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate”. If approved, Glyxambi will be the first SGLT2/DPP-4 FDC to enter the market.

1.1 Recommendation The Office of Clinical Pharmacology (OCP) has reviewed the clinical pharmacology data submitted under NDA 206073 and finds it acceptable to support the approval.

1.2 Phase IV Commitments None.

1.3 Summary of Important Clinical Pharmacology Findings Empagliflozin / linagliptin film-coated tablets, (Glyxambi) are manufactured in strengths of 10 mg / 5 mg, and 25 mg / 5 mg, and contain 10 mg or 25 mg of empagliflozin and 5 mg of linagliptin. The sponsor has proposed the recommended starting dose of Glyxambi of 10 mg empagliflozin/5 mg linagliptin once daily. In patients who require additional glycemic control, the dose can be increased to 25 mg empagliflozin / 5 mg linagliptin once daily. The sponsor also proposed that Glyxambi can be taken with or without food. This NDA is supported by data from one bioequivalence (BE) and food-effect trial (Study 1275.3), one multiple-dose relative bioavailability study (Study 1245.3), and one safety and efficacy trial (1275.1). Evaluation of BE portion of study 1275.3 was conducted by the ONDQA reviewer. The review has concluded that the proposed tablet containing 25 mg empagliflozin and 5 mg linagliptin is bioequivalent to the individual tablets administered together (see review by Dr. Kareen Riviere in DARRTS dated 09/16/2014). The multiple-dose relative bioavailability study (Study 1245.3) has already been reviewed under NDA 204629 (see Clinical Pharmacology review by Dr. Manoj Khurana in DARRTS dated 11/08/2013). In brief, relative bioavailability of empagliflozin and of linagliptin after concomitant multiple oral administration of 50 mg empagliflozin tablets and 5 mg linagliptin were evaluated in comparison to 50 mg empagliflozin and 5 mg linagliptin given alone. The steady-state bioavailability of 5 mg linagliptin q.d. (based on AUCτ,ss and Cmax,ss) was not affected by concomitant administration of 50 mg empagliflozin q.d. The 90% confidence intervals of the adjusted geometric mean ratios for linagliptin were completely located within the limits of 80 to 125%. For empagliflozin, the AUCτ,ss was similar when the drug was given alone and in combination with linagliptin, but Cmax,ss was reduced by approximately 12% when the drug was co-administered with linagliptin. The clinical pharmacology review of the food effect portion of study 1275.3 showed that:


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2.1.4 What are the proposed dosages and routes of administration? The proposed starting dose of Glyxambi is 10 mg empagliflozin/5 mg linagliptin once daily, administered orally. In patients who require additional glycemic control, the dose can be increased to 25 mg empagliflozin/5 mg linagliptin once daily.

2.2 General Clinical Pharmacology 2.2.1 What is known about the PK characteristics of Empagliflozin and Linagliptin following the

administration of approved drugs, Jardiance and Tradjenta tablets?

Empagliflozin: After single dose administration of 10 mg or 25 mg empagliflozin tablet formulations under fasted conditions, empagliflozin was absorbed rapidly with a median Tmax of 1 hour for both doses. Thereafter, plasma levels declined in a biphasic fashion with a rapid distribution phase and a slower elimination phase. Empagliflozin exposure increased in proportion to the dose. Mean (%CV) AUC0-x was 2360 nmol·h/L (26.7%) for the 10 mg dose and 5550 nmol·h/L (26.0%) for the 25 mg dose. Mean (%CV) Cmax was 377 nmol/L (26.2%) and 867 nmol/L (26.8%) for the 10 mg and 25 mg dose, respectively. The apparent steady-state volume of distribution ranged from 180-230 L. Following administration of an oral [14C]-empagliflozin solution (50 mg; ~100μCi) to healthy subjects, the total radioactivity exposure in blood was lower compared to plasma, consistent with moderate red blood cell (RBC) partitioning (28.6% to 36.8%) observed in vivo. Protein binding of total radioactivity ranged from 80.3% to 86.2%. No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O, 3-O, and 6-O glucuronide). Systemic exposure of each metabolite was less than 10% of total drug related material. O-dealkylation gave rise to metabolite M380/1 (EX 609), an active metabolite of empagliflozin, which was not detected in plasma after single oral doses of 0.5 to 50 mg empagliflozin; only partial profiles were obtained at doses of 100 to 800 mg empagliflozin. At the highest dose level, the EX 609 metabolite exposure (AUC and Cmax) was approximately 0.12% of the parent drug. The total fraction of EX 609 excreted in urine ranged from 0.02 to 0.05% of the administered empagliflozin dose. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. The typical apparent terminal elimination half-life of empagliflozin was 12.4 h and typical apparent oral clearance was 10.6 L/h. Mass balance study showed that overall drug related radioactivity recovered in urine and feces over the 168 h study period was 95.6%. A mean of 54.4% of the dose was excreted in urine and 41.2% was excreted in feces. Approximately 50% of the drug related radioactivity excreted in urine was unchanged parent (28.6%). PKPD studies in subjects with normal renal function in general showed that fraction of empagliflozin dose excreted unchanged ranged from 13- 18%. With once-daily dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent with half-life, up to 22% accumulation of empagliflozin was observed. Population pharmacokinetic/pharmacodynamic analyses suggest that dose-adjustments of Empagliflozin is not warranted based on covariates such as eGFR, body weight, age, BMI, race, and gender.


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In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and subjects with kidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR. No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2. Empagliflozin should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2. In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function. Linagliptin: Linagliptin follows non-linear PK for doses ranging from 1 mg to 600 mg. Increases in exposures were less than dose proportional for the dose range of 1 mg to 10 mg, more than dose proportional for the dose range of 25 mg to 100 mg, and almost dose proportional for the dose range of 100 mg to 600 mg. The non-linearity in dose range of 1 to 10 mg and long half-life of linagliptin (i.e., >100 hours) may be explained by concentration dependent binding to DPP-4. At concentrations of 1 nM, almost 99% of drug remains bound to DPP-4, which reduced to 70-80% at concentrations of about 100 nM. Following oral administration, Tmax is reached between 0.5 to 3 h. The accumulation half-life of linagliptin ranged from 8-12 hours. Metabolism is a minor pathway of elimination for linagliptin. The majority of drug is eliminated unchanged in feces (~85%) and a minor proportion in urine (~4.5%). Enterohepatic circulation contributes to linagliptin elimination. The predominant metabolite, CD1790 (formed by CYP3A4 isoform), is therapeutically inactive. Co-administration with high-fat meal reduced linagliptin rate of absorption (i.e., Cmax) by ~15 to 25% but had no effect on AUC. These changes were not considered clinically relevant. • Population PK analysis suggested that the between subject variability on clearance was low (i.e., CV% of 24%). Gamma glutamyl transferase (GGT) was a significant covariate for clearance but had no clinically meaningful effect. No dose-adjustments are recommended for subjects with renal or hepatic impairment. Age, weight, BMI, and gender had no clinically meaningful effect of linagliptin PK. Linagliptin exposures in subjects with Japanese and Chinese ethnicity were ~25-30% higher than that of Caucasian subjects. This small change was not expected to be clinically meaningful. 2.2.2 Were the active moieties in the plasma appropriately identified and measured to assess the

pharmacokinetics? Yes. Empagliflozin and Linagliptin were appropriately identified and measured in plasma to assess the PK parameters.


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2.3 Intrinsic Factors 2.3.1 What intrinsic factors (e.g., weight, gender, race, age, height, disease, genetic polymorphism,

pregnancy, and organ dysfunction) influence exposure (PK usually) and/or response, and what is the impact of any differences in exposure on efficacy or safety responses?

No dedicated study was conducted with Glyxambi to evaluate the pharmacokinetics in special populations such as geriatric, hepatic impaired and renal impaired patients. The Applicant referred to information regarding special population (geriatric and renal) and drug interaction from the NDAs for Jardiance (Empagliflozin, NDA 204629) and Tradjenta (Linagliptin, NDA 201280).

2.4 Extrinsic Factors 2.4.1 What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence

exposure and/or response and what is the impact of any differences in exposure on pharmacodynamics?

The effects of herbal products, smoking and alcohol on Glyxambi use were not evaluated. The sponsor conducted a specific study to investigate the effect of food on the PK of Glyxambi. This is discussed in the next section below.

2.5 General Biopharmaceutics The sponsor conducted a relative bioavailability study to evaluate the pharmacokinetics of empagliflozin and linagliptin from the FDC tablet containing 25 mg empagliflozin and 5 mg linagliptin compared to the individual tablets administered together. This study also evaluated a second FDC formulation (A3), however, the data for this formulation will not be discussed in this review since this formulation does not represent the to-be-commercialized formulation. 2.5.1 Was bioequivalence established between Empagliflozin and Linagliptin FDC formulations and

individual components? Bioequivalence portion of this study entitled “Relative bioavailability investigations of a 25 mg empagliflozin / 5 mg linagliptin fixed dose combination (FDC) tablet (formulation A1) including the comparison with its mono-components, the comparison with a second FDC tablet (formulation A3), and the investigation of food (an open-label, randomized, single dose, crossover, Phase I trial in healthy male and female volunteers)” was evaluated by ONDQA. For details, please refer to the review by Dr. Kareen Riviere in DARRTS. Briefly, the pharmacokinetic data demonstrate that the proposed tablet containing 25 mg empagliflozin and 5 mg linagliptin (formulation A1) is bioequivalent to the co-administered individual components.


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The sponsor has proposed that the recommended starting dose of Glyxambi be 10 mg empagliflozin/5 mg linagliptin once daily. In patients who require additional glycemic control, the dose can be increased to 25 mg empagliflozin/5 mg linagliptin once daily. However, the additional benefit from 25 mg empagliflozin/5 mg linagliptin once daily appears to be available only in select treatment settings (add-on to metformin in this case) as demonstrated by the data.

2.7 Analytical 2.7.1 Is the analytical method for Empagliflozin and Linagliptin appropriately validated? Empagliflozin: Empagliflozin in human plasma was measured using a LC-MS/MS assay. The method was validated for a range of 1.11-1110 nmol/L, based on the analysis of 0.150 mL of plasma. Briefly, empagliflozin is extracted from EDTA human plasma by solid phase supported liquid extraction (SLE+). Before the extraction, isotope-labeled drug is added as an internal standard. The sample is transferred to a 96-well diatomaceous earth extraction plate (SLE+) and allowed to absorb. The analytes are eluted with isopropyl acetate. The eluate is evaporated to dryness and the samples reconstituted with acetonitrile/water. The reconstituted samples are injected into an LC-MS/MS system using a C6-phenyl column with an ammonium acetate/acetonitrile/water mobile phase. Linagliptin: Linagliptin in human plasma was measured using a HPLC-MS/MS assay by

. The method was validated for a range of 0.100 – 20.0 ng/mL, based on the analysis of 0.150 mL of plasma. . The samples were extracted by solid phase extraction (SPE), transferred to 96-well SPE plate and washed with acetic acid and methanol. The samples were then eluted from the packing material into fresh 96 –well plates with ammonia in methanol and formic acid. The plates were capped, vortex mixed, centrifuged and submitted for HPLC-MS/MS analysis. Linagliptin was detected and quantified using a tandem mass spectrometer in the positive ionization mode and an injection volume of approximately 30 μL. The ion masses monitored were 473.1/420.2 (± 0.5 Da) for Linagliptin and 476.2/423.2 (± 0.5 Da) for [13C3] Linagliptin. Additionally, the ion masses for the metabolite CD 1750 XX (474.2/421.3 (± 0.5 Da)) and [13C3]CD 1750 XX (477.2/424.2 (± 0.5 Da)) were monitored in this study, however they were not quantified. A summary of key descriptive parameters for the bioanalytical assays used in clinical studies is listed in Table 13.


(b) (4)

(b) (4)

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3 Labeling Comments (Preliminary) The following are the labeling recommendations relevant to clinical pharmacology for NDA . The red strikeout font is used to show the proposed text to be deleted and underline blue font to show text to be included or comments communicated to the sponsor.


(b) (4)

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.1 Mechanism of Action TRADENAMEGLYXAMBI TRADENAME GLYXAMBI combines 2 antihyperglycemic agents with different complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter (SGLT2) inhibitor, and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Empagliflozin Sodium glucose co transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Linagliptin Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. 12.2 Pharmacodynamics Empagliflozin Urinary Glucose Excretion In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily. Urinary Volume In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment. Cardiac Electrophysiology In a randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered a single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin. Linagliptin Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures. Cardiac Electrophysiology


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In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose. 12.3 Pharmacokinetics TRADENAME GLYXAMBI The results of the bioequivalence study in healthy subjects demonstrated that TRADENAME GLYXAMBI (25 mg empagliflozin/5 mg linagliptin) combination tablets are bioequivalent to coadministration of corresponding doses of empagliflozin and linagliptin as individual tablets. Administration of the fixed-dose combination with food resulted in no change in overall exposure of empagliflozin or linagliptin; however, the peak exposure was decreased by 39% and 32% for empagliflozin and linagliptin, respectively. These changes are not likely to be clinically significant. Absorption Empagliflozin The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol·h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time. Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food. Linagliptin The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. Linagliptin may be administered with or without food. Distribution Empagliflozin The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%. Linagliptin The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.


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Metabolism Empagliflozin No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Linagliptin Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. Elimination Empagliflozin The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug. Linagliptin Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min. Specific Populations Renal Impairment TRADENAMEGLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of TRADENAME GLYXAMBI in renally impaired patients have not been performed [see Dosage and Administration (2.3)]. Empagliflozin: In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and subjects with kidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR. Linagliptin: An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes and severe renal impairment (CrCl <30 mL/min), and 11 patients with type 2 diabetes and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula. Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.


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In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with type 2 diabetes and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2 diabetes groups, renal excretion was below 7% of the administered dose. These findings were further supported by the results of population pharmacokinetic analyses. Hepatic Impairment TRADENAME GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of TRADENAME GLYXAMBI in hepatically impaired patients have not been performed. Empagliflozin: In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75% and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function. Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition. Effects of Age, Body Mass Index, Gender, and Race Empagliflozin: Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations (8.5)]. Linagliptin: Based on the population PK analysis, age, body mass index (BMI), gender and race do not have a clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (8.5)]. Pediatric Studies characterizing the pharmacokinetics of empagliflozin or linagliptin after administration of TRADENAME GLYXAMBI in pediatric patients have not been performed. Drug Interactions Pharmacokinetic drug interaction studies with TRADENAME GLYXAMBI have not been performed; however, such studies have been conducted with the individual components of TRADENAME GLYXAMBI (empagliflozin and linagliptin). Empagliflozin In vitro Assessment of Drug Interactions In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin also does not inhibit UGT1A1. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated. Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake


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transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters. In vivo Assessment of Drug Interactions No dose adjustment of empagliflozin is recommended when coadministered with commonly prescribed medicinal products based on results of the described pharmacokinetic studies. Empagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, hydrochlorothiazide, and torasemide in healthy volunteers (see Figure 1). The observed increases in overall exposure (AUC) of empagliflozin following coadministration with gemfibrozil, rifampicin, or probenecid are not clinically relevant. In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown.


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Table 3 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin

Coadministered Drug

Dosing of Coadministered Drug*

Dosing of Linagliptin*

Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.0 AUC† Cmax

No dosing adjustments required for linagliptin when given with the following coadministered drugs:

Metformin 850 mg TID 10 mg QD 1.20 1.03

Glyburide 1.75 mg# 5 mg QD 1.02 1.01

Pioglitazone 45 mg QD 10 mg QD 1.13 1.07

Ritonavir 200 mg BID 5 mg# 2.01 2.96 The efficacy of linagliptin may be reduced when administered in combination with strong inducers of CYP3A4 or P-gp (e.g., rifampin). Use of alternative treatments is strongly recommended [see Drug Interactions (7.2)]. Rifampin 600 mg QD 5 mg QD 0.60 0.56 *Multiple dose (steady state) unless otherwise noted #Single dose †AUC = AUC(0 to 24 hours) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments QD = once daily BID = twice daily TID = three times daily Table 4 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs

Coadministered Drug

Dosing of Coadministered Drug*

Dosing of Linagliptin*

Geometric Mean Ratio (ratio with/without coadministered drug)

No effect = 1.0

AUC† Cmax

No dosing adjustments required for the following coadministered drugs:

Metformin 850 mg TID 10 mg QD metformin 1.01 0.89

Glyburide 1.75 mg# 5 mg QD glyburide 0.86 0.86

Pioglitazone 45 mg QD 10 mg QD pioglitazone metabolite M-III metabolite M-IV

0.94 0.98 1.04

0.86 0.96 1.05

Digoxin 0.25 mg QD 5 mg QD digoxin 1.02 0.94

Simvastatin 40 mg QD 10 mg QD simvastatin simvastatin acid

1.34 1.33

1.10 1.21

Warfarin 10 mg# 5 mg QD

R-warfarin S-warfarin INR PT

0.99 1.03 0.93** 1.03**

1.00 1.01 1.04** 1.15**

Ethinylestradiol and levonorgestrel

ethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD 5 mg QD ethinylestradiol

levonorgestrel 1.01 1.09

1.08 1.13

*Multiple dose (steady state) unless otherwise noted #Single dose †AUC = AUC(INF) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments **AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic end points INR = International Normalized Ratio PT = Prothrombin Time QD = once daily TID = three times daily


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4 APPENDIX

OCP Filing Memo


Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for NDA_BLA or Supplement

Lokesh Jain 14 Mar, 2014 Team Leader Date



SURYANARAYANA M SISTA10/07/2014

MANOJ KHURANA10/07/2014


1

BIOPHARMACEUTICS REVIEWOffice of New Drug Quality Assessment

Application No.: NDA 206-073Reviewer: Kareen Riviere, Ph.D.

Submission Date(s): 1/30/14; 6/3/14

Division: DMEP Secondary Signature: Tapash Ghosh, Ph.D.

Applicant:Boehringer Ingelheim Pharmaceuticals, Inc.

Supervisor: Paul Seo, Ph.D.

Trade Name: Glyxambi Date Assigned:

1/30/14

Generic Name: empagliflozin/linagliptin fixed-dose combination tablets

Date of Review:

9/16/14

Indication: adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Type of Submission: 505(b)(1) New Drug Application

Formulation/strengths: IR Tablet; 10 mg/5 mg and 25 mg/5mg

Route of Administration:

Oral

SUMMARY:

This submission is a 505(b)(1) New Drug Application for 10 mg/5 mg and 25 mg/5mg of Glyxambi (empagliflozin/linagliptin) fixed-dose combination tablets. The proposed indication is for adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate.

The Biopharmaceutics review for this NDA is focused on the evaluation and acceptability of 1) using the disintegration testing in lieu of dissolution testing, 2) the proposed dissolution method and acceptance criterion for supporting post-approval changes, and 3) the relative bioavailability data of the FDC tablet containing 25 mg BI 10773 and 5 mg linagliptin compared to the individual tablets administered together.

A. Relative Bioavailability Study

The main purpose of Study 1275.3 was to investigate the relative bioavailability of the FDC tablet containing 25 mg empagliflozin and 5 mg linagliptin compared to the individual tablets administered together. The study title is “Relative bioavailability investigations of a 25 mg empagliflozin / 5 mg linagliptin fixed dose combination (FDC) tablet (formulation A1) including the comparison with its mono-components, the comparison with a second FDC tablet (formulation A3), and the investigation of food (an open-label, randomized, single dose, crossover, Phase I trial in healthy male and female volunteers)”.

The BE data demonstrate that the proposed tablet containing 25 mg empagliflozin and 5 mg linagliptin is bioequivalent to the individual tablets administered together.

B. Dissolution Method

The proposed dissolution acceptance method (for supporting post-approval changes) is:

USPApparatus

Rotation Speed

MediaVolume

Temp Medium

2 50 rpm 900 ml 37 °C pH 6.8 phosphate buffer

The proposed dissolution method is deemed acceptable for supporting post-approval changes.


3

ASSESSMENT OF BIOPHARMACEUTICS INFORMATION

1. Background

Drug Substance

The chemical structures of both substances are shown in Figures 1 and 2.

Figure 1. Chemical Structure of empagliflozin

Figure 2. Chemical Structure of linagliptin

The Applicant claims that both APIs are BCS Class 3 drugs substances. The solubility profile and intrinsic dissolution profile of empagliflozin are shown in Tables 1 and 2, respectively.

Table 1. Solubility of Empagliflozin at 37 °C in Different Medium pH

Table 2. Intrinsic Dissolution Rates of Empagliflozin at 37 °C in Aqueous Media

The solubility profile and intrinsic dissolution profile of linagliptin are shown in Tables 3 and 4, respectively.


4

Table 3. Solubility of Linagliptin at 37 °C in Different Medium pH

Table 4. Intrinsic Dissolution Rates of Linagliptin at 37 °C in Aqueous Media

Reviewer’s Assessment:Table 1 shows that empagliflozin solubility ranges from 0.4 – 0.5 mg/mL from pH 1 to 7.5 at 37 °C. For the high strength tablet, the dose to solubility volume range is 25mg/0.5 mg/mL to 25mg/0.4 mg/mL which correspond to 50 mL to 62.5 mL. Hence, empagliflozin is considered highly soluble within the physiological pH range. Also,this table shows that sink conditions are achieved for empagliflozin in the proposed medium (900 mL of pH 6.8 buffer) since a solubility of 360 mg/900 ml is achieved which is more than three times the solubility needed (i.e., 3 x 25 mg/900 mL).

Table 3 shows that linagliptin solubility ranges from 2.8 to at least 10 mg/mL from pH 1 to 7.5 at 37 °C. For the high strength of 5 mg, the dose to solubility volume range is 5mg/10 mg/mL to 5mg/2.9mg/mL which corresponds to 0.5mL to 1.79 mL. Hence, linagliptin is considered highly soluble within the physiological pH range. Also this table shows that sink conditions are achieved for linagliptin in the proposed medium (900 mL of pH 6.8 buffer) since a solubility of 2520 mg/900 ml is achieved, which is more than 3 times the solubility needed (i.e., 5 mg/900 mL).

Drug Product

Boehringer Ingelheim has developed two strength of empagliflozin + linagliptin fixed-dose combination(FDC) tablets (25 mg empagliflozin + 5 mg linagliptin and 10 mg empagliflozin + 5 mg linagliptin) for once daily administration. The Applicant conducted two phase 1 trials and one phase 3 trial. The Phase 3


6

Reviewer’s Assessment:

2. BE Studies

The main purpose of Study 1275.3 was to investigate the relative bioavailability of the FDC tablet containing 25 mg empagliflozin and 5 mg linagliptin compared to the individual tablets administered together. The study title is “Relative bioavailability investigations of a 25 mg empagliflozin / 5 mg linagliptin fixed dose combination (FDC) tablet (formulation A1) including the comparison with its mono-components, the comparison with a second FDC tablet (formulation A3), and the investigation of food (an open-label, randomized, single dose, crossover, Phase I trial in healthy male and female volunteers)”.

The mean plasma concentration-time profiles of empagliflozin are shown in Figure 3.

Figure 3. Geometric Mean Plasma Concentration-Time Profiles of Empagliflozin after Single Oral Administration of 25 mg Empagliflozin and 5 mg Linagliptin as FDC A1 Tablet (N=42) or Individual Tablets (N=40)

The mean pharmacokinetic parameters for empagliflozin are displayed in Table 7.

Table 7. Mean Pharmacokinetic Parameters for Empagliflozin by Treatment

The mean plasma concentration-time profiles of linagliptin are shown in Figure 4.


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7

Figure 4. Geometric Mean Plasma Concentration-Time Profiles of Linagliptin after Single Oral Administration of 25 mg Empagliflozin and 5 mg Linagliptin as FDC A1 Tablet (N=42) or Individual Tablets (N=40)

The mean pharmacokinetic parameters for linagliptin are displayed in Table 8.

Table 8. Mean Pharmacokinetic Parameters for Linagliptin by Treatment

The bioequivalence data for Study 1275.3 is presented in Table 9.

Table 9. gMeans and 90% Confidence Interval of the gMean Ratio for the Primary Pharmacokinetic Parameters of Empagliflozin and Linagliptin after Administration of 25 mg Empagliflozin and 5 mg Linagliptin as FDC A1 Tablet

and Individual Tablets

Reviewer’s Assessment:The BE study design as well as the bioanalytical method development and validation report are adequate.


10

The Applicant selected phosphate buffer pH 6.8 as the appropriate dissolution medium for empagliflozin/ linagliptin film-coated tablets .

Reviewer’s Assessment:Both strengths of the drug product have rapid dissolution (dissolution > % in 15 minutes) at pH 1.2, 4.0, and 6.8) for both drug substances. Thus, the selection of dissolution medium is justified.

Discriminating Ability of the Dissolution Method

The Applicant selected several variables that might affect tablet dissolution to investigate the discriminating abilityof the proposed method. These variables include different types of formulations, different compression forcesresulting in different tablet hardness, and different particle sizes of both active ingredients.

Influence of Magnesium Stearate Content

Figures 8 and 9 show the effect of different amounts of magnesium stearate on the dissolution profiles for both strength products.


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11

Influence of Content

Influence of Film Coat

Figure 11 shows the influence of the film-coat on dissolution.


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12

Influence of Drug Substance Particle Size

The Applicant evaluated the influence of the particle size of empagliflozin on dissolution (see Figure 14 and 15).


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21

Figure 25. Impact of Different Formulation Types on Disintegration Time, Clinical Batches Study 1275.3, Film-

To derive the specification for disintegration, the Applicant used release results of clinical, stability and primarystability batches as well as results obtained during long-term and accelerated stability study for the statistical evaluation under consideration of the following prerequisites:• The stage testing concept according to USP is included in the statistical evaluation• Confidence level of 0.95 is applied based on the statistical evaluation a specification limit of min:sec was calculated under above mentioned conditions.

Figure 26 shows the mean disintegration times of all considered release and stability data and their standard deviation.

Figure 26. Impact of a proposed specification limit based on the tolerance interval approach for the objectives 'Acceptance at Stage 1 or 2 and the confidence level 0.95'.


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22

Reviewer’s Assessment:According to ICH Q6A, disintegration testing in lieu of dissolution testing is appropriate if the following conditions are met:

a. The drug(s) has high solubility (dose/solubility ≤ 250 mL) throughout the physiological pH range (pH 1.2-6.8),

b. The drug product has rapid dissolution (dissolution > % in 15 minutes at pH 1.2, 4.0, and 6.8), andc. A relationship has been determined between disintegration and dissolution, or disintegration is shown to

be more discriminating than dissolution.

The Applicant has shown that both drugs have high solubility throughout the physiological pH range (pH 1.2-6.8). Refer to discussion in section 1 above. Additionally, the dissolution data in Figures 6 and 7 demonstrate that the drug product has rapid dissolution (dissolution > % in 15 minutes at pH 1.2, 4.0, and 6.8). Thus, the proposed product could meet a dissolution acceptance criterion of Q= % at 15 minutes.

Furthermore, the dissolution rate correlates with the disintegration time of the empagliflozin / linagliptin film-coated tablets. The results show that in the time range of complete disintegration in the vessel (about minutes) approximately % of both active ingredients are dissolved (see Tables13 and 14). Therefore, it can be seen that the dissolution process is mainly influenced by the disintegration process. Figures 17 and 18 also demonstrate a relationship between dissolution and disintegration.

Lastly, the disintegration and dissolution method seems to have similar discriminating ability. Figures 19 to 23 shows that changes in some formulation and manudactuing variables led to changes in the disinigertation time.Also the data in Figure 25 and Table 12 demonstrate that although slow and fast releasing batches have markedly different disintegration times, both batches can be considered bioequivalent based on the results of Study 1275.3. This same phenomenon was obtained with the proposed dissolution method. These data suggest that the disintegration and dissolution method can be somewhat over discriminating.

Thus, the Applicant’s proposal to use disintegration testing in lieu of dissolution testing is acceptable.Additionally, the proposed disintegration acceptance crietrion is adequate.


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Office of Clinical Pharmacology

New Drug Application Filing and Review Form General Information About the Submission

Information Information NDA/BLA Number 206073 Brand Name Glyxambi OCP Division (I, II, III, IV, V) II Generic Name Empagliflozin +

Linagliptin FDC Medical Division DMEP Drug Class SGLT2 inhibitor and

DPP-4 inhibitor combination product

OCP Reviewer Suryanarayana Sista, Ph.D. Indication(s) Treatment of Type 2 diabetes

OCP Team Leader Lokesh Jain, Ph.D. Dosage Form oral tablet Pharmacometrics Reviewer Dosing Regimen see belowa

Date of Submission 01/30/2014 Route of Administration oral Estimated Due Date of OCP Review Sponsor Boehringer Ingelheim

Pharmaceuticals, Inc. Medical Division Due Date Priority Classification 505 (b)(1) Standard PDUFA Due Date 01/30/2015

a • The recommended starting dose of Glyxambi is 10 mg empagliflozin/5 mg linagliptin once daily. In patients who require additional glycemic control,

the dose can be increased to 25 mg empagliflozin/5 mg linagliptin once daily. • Glyxambi can be taken with or without food.

Clinical Pharmacology and Biopharmaceutics Information “X” if included

at filing Number of

studies submitted

Number of studies

reviewed

Study Nos./Critical Comments If any

STUDY TYPE

Table of Contents present and sufficient to locate reports, tables, data, etc.

X

Tabular Listing of All Human Studies X 3 1275.3, 1245.30, 1275.1 HPK Summary Labeling X Reference Bioanalytical and Analytical Methods

X

I. Clinical Pharmacology Mass balance: Isozyme characterization: Human Biomaterials: Blood/plasma ratio: Plasma protein binding: Pharmacokinetics (e.g., Phase I) X 2 1275.3, 1245.30

Healthy Volunteers-

single dose: multiple dose: X 1a 1245.30

Patients-

single dose: multiple dose:

Dose proportionality - fasting / non-fasting single dose:

fasting / non-fasting multiple dose: Drug-drug interaction studies -

in-vivo effects on primary drug: in-vivo effects of primary drug:

in-vitro: Subpopulation studies -



Clinical Pharmacology and Biopharmaceutics Information “X” if included

at filing Number of

studies submitted

Number of studies

reviewed

Study Nos./Critical Comments If any

ethnicity: gender:

pediatrics: geriatrics:

renal impairment: hepatic impairment:

PD - Phase 1: Phase 2: Phase 3: X 1 1275.1

PK/PD - Phase 1 and/or 2, proof of concept:

Phase 3 clinical trial: Population Analyses -

Data rich: Data sparse:

II. Biopharmaceutics Absolute bioavailability Relative bioavailability -

solution as reference: alternate formulation as reference:

Bioequivalence studies - traditional design; single / multi dose: X 1a 1275.3

replicate design; single / multi dose: Food-drug interaction studies X 1a 1275.3 Bio-waiver request based on BCS Not Applicable BCS class Not Applicable Dissolution study to evaluate alcohol

induced dose-dumping Not Applicable

III. Other CPB Studies Genotype/phenotype studies Chronopharmacokinetics Pediatric development plan Literature References Total Number of Studies 3

aStudy counted more than once Brief summary about the submission: Boehringer Ingelheim Pharmaceuticals, Incorporated Inc. are seeking US marketing approval for Empagliflozin+Linagliptin FDC tablets (Trade Name: Glyxambi) under the provisions of Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act. The proposed indication of Glyxambi tablets is “adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate”. This NDA is supported by data from one bioequivalence and food-effect trial, one multiple-dose relative bioavailability study and one efficacy trial.



Type of Study / Study Identifier Location of Study Report

Objective(s) of the Study Study Design

Phase I BE study / 1275.3 Section 5.3.1.2

To evaluate the relative BA of 25 mg empagliflozin + 5 mg linagliptin FDC (formulation A1), including the comparison with the monocomponents, a second FDC (formulation A3), and the effect of food

Open-label, randomized, single-dose, crossover, Phase I study

• Treatment A: FDC formulation A1 tablets/fasted-oral once daily

• Treatment B: BI 10773 + linagliptin as individual tablets/fasted –oral once daily

• Treatment C: FDC A1 tablets/fed condition-oral once daily

• Treatment D: FDC A3 tablets ( formulation)/fasted oral once daily

Phase I PK study / 1245.30 Section 5.3.3.4

To evaluate the relative BA of multiple doses of BI 10773 50 mg and linagliptin 5 mg after concomitant administration compared to multiple doses of BI 10773 50 mg and linalgiptin 5 mg administered alone

Open-label, randomized, cross-over, Phase I study • Empagliflozin 25 mg (2 tablets of 25 mg)-oral once

daily • Linagliptin 5 mg tablets-oral once daily

Phase III Efficacy and Safety study / 1275.1 Section 5.3.5.1

To evaluate the efficacy and safety of empagliflozin (10 mg or 25 mg) + linagliptin fixeddose combination (FDC) compared to the individual components in treatment naïve and metformin treated patients

Randomized, double-blind, active controlled, parallel group, Phase III study

• Empagliflozin 25 mg + linagliptin 5 mg (E25+L5) FDC tablets-oral once daily

• Empagliflozin 10 mg + linagliptin 5 mg (E10+L5) FDC tablets-oral once daily

• Empagliflozin 10 mg (E10) tablets oral once daily • Empagliflozin 25 mg (E25) tablets oral once daily • Linagliptin 5 mg (L5) tablets-oral once daily


(b) (4)


On initial review of the NDA/BLA application for filing:

Content Parameter Yes No N/A Comment Criteria for Refusal to File (RTF) 1 Has the applicant submitted bioequivalence data comparing to-be-marketed

product(s) and those used in the pivotal clinical trials? X Pivotal clinical trial used the

to be marketed formulation 2 Has the applicant provided metabolism and drug-drug interaction

information? X Data in original approved NDA

for linagliptin and NDA under review for Empagliflozin

3 Has the sponsor submitted bioavailability data satisfying the CFR requirements?

X Data also in original approved NDA for linagliptin and NDA under review for Empagliflozin

4 Did the sponsor submit data to allow the evaluation of the validity of the analytical assay?

X

5 Has a rationale for dose selection been submitted? X Data in original approved NDA for linagliptin and NDA under review for Empagliflozin

6 Is the clinical pharmacology and biopharmaceutics section of the NDA organized, indexed and paginated in a manner to allow substantive review to begin?

X

7 Is the clinical pharmacology and biopharmaceutics section of the NDA legible so that a substantive review can begin?

X

8 Is the electronic submission searchable, does it have appropriate hyperlinks and do the hyperlinks work?

X

Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality) Data 9 Are the data sets, as requested during pre-submission discussions, submitted

in the appropriate format (e.g., CDISC)? X

10 If applicable, are the pharmacogenomic data sets submitted in the appropriate format?

X

Studies and Analyses 11 Is the appropriate pharmacokinetic information submitted? X Data also in original approved

NDA for linagliptin and NDA under review for Empagliflozin

12 Has the applicant made an appropriate attempt to determine reasonable dose individualization strategies for this product (i.e., appropriately designed and analyzed dose-ranging or pivotal studies)?

X Data in original approved NDA for linagliptin and NDA under review for Empagliflozin

13 Are the appropriate exposure-response (for desired and undesired effects) analyses conducted and submitted as described in the Exposure-Response guidance?

X

14 Is there an adequate attempt by the applicant to use exposure-response relationships in order to assess the need for dose adjustments for intrinsic/extrinsic factors that might affect the pharmacokinetic or pharmacodynamics?

X Data in original approved NDA for linagliptin and NDA under review for Empagliflozin

15 Are the pediatric exclusivity studies adequately designed to demonstrate effectiveness, if the drug is indeed effective?

X

16 Did the applicant submit all the pediatric exclusivity data, as described in the WR?

X

17 Is there adequate information on the pharmacokinetics and exposure-response in the clinical pharmacology section of the label?

X

General 18 Are the clinical pharmacology and biopharmaceutics studies of appropriate

design and breadth of investigation to meet basic requirements for approvability of this product?

X

19 Was the translation (of study reports or other study information) from another language needed and provided in this submission?

X

IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE? Yes

If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and provide comments to be sent to the Applicant. Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter.



Comment to Sponsor: None. Suryanarayana M. Sista 14 Mar, 2014 Reviewing Clinical Pharmacologist Date Lokesh Jain 14 Mar, 2014 Team Leader Date



SURYANARAYANA M SISTA03/31/2014

LOKESH JAIN04/08/2014


PRODUCT QUALITY - BIOPHARMACEUTICS

FILING REVIEW

File name: NDA 206-073 Product Quality - Biopharmaceutics Filing Review Page 3

INITIAL BIOPHARMACEUTICS ASSESSMENT

Boehringer Ingelheim has developed two strength of empagliflozin + linagliptin fixed-dose combination tablets (25 mg empagliflozin + 5 mg linagliptin and 10 mg empagliflozin + 5 mg linagliptin) for once daily administration. The Applicant conducted two phase 1 trials and one phase 3 trial. The Phase 3 study evaluated two doses of the empagliflozin/linagliptin tablets (25 mg empagliflozin/5 mg linagliptin and 10 mg empagliflozin/5 mg linagliptin) for 52 weeks. The final commercial formulation was used in the phase 3 study.

BE Study The main purpose of Study 1275.3 was to investigate the relative bioavailability of the FDC tablet containing 25 mg BI 10773 and 5 mg linagliptin compared to the individual tablets administered together. The study title is “Relative bioavailability investigations of a 25 mg BI 10773 / 5 mg linagliptin fixed dose combination (FDC) tablet (formulation A1) including the comparison with its mono-components, the comparison with a second FDC tablet (formulation A3), and the investigation of food (an open-label, randomised, single dose, crossover, Phase I trial in healthy male and female volunteers)”.

Figure 1. Geometric mean plasma concentration-time profiles of BI 10773 after single oral administration of 25 mg BI 10773 and 5 mg linagliptin as FDC A1 tablet (N=42) or individual tablets (N=40)

Table 1. Mean Pharmacokinetic Parameters of BI 10773 by Treatment


PRODUCT QUALITY - BIOPHARMACEUTICS

FILING REVIEW

File name: NDA 206-073 Product Quality - Biopharmaceutics Filing Review Page 5

USPApparatus

Rotation Speed

MediaVolume

Temp Medium

2 50 rpm 900 ml 37 °C pH 6.8 phosphate buffer

The proposed dissolution acceptance criterion is:

Acceptance Criterion

Q = % at 30 min

The Biopharmaceutics review for this NDA will be focused on the evaluation and acceptability of 1) using the disintegration testing in lieu of dissolution testing, 2) the proposed dissolution method and acceptance criterionfor supporting post-approval changes, and 3) the relative bioavailability data of the FDC tablet containing 25 mg BI 10773 and 5 mg linagliptin compared to the individual tablets administered together.

To aid the review of the Applicant’s submission, the following comment should be conveyed to the Applicant: 1. Provide supportive validation data for the dissolution method (i.e., method robustness, etc.) and

analytical method (precision, accuracy, linearity, stability, etc.).2. Submit SAS Transport files of the pharmacokinetic data from the BE study. The data should include

AUC0-t, AUC0-inf, Cmax, Tmax, Kel, and T1/2 as shown. Please submit the data in the following format:

SUBJ SEQ PER TRT AUCT AUCI CMAX TMAX KE Thalf

RECOMMENDATION: The ONDQA Biopharmaceutics team has reviewed NDA 206-037 for filing purposes. We found this NDA fileable from a Biopharmaceutics perspective. The Applicant has submitted a reviewable submission.


(b) (4)





Documents

206073Orig1s000 - Food and Drug Administration...Page 1 of 45 Reference ID: 3640237 OFFICE OF CLINICAL PHARMACOLOGY REVIEW. NDA: 206073 Submission Date(s): January 30, 2014 . Brand