CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201281Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`REV-NONCLINICAL—OS (Review Noted (NAI))
`NDA-20 128 1
`ORIG-l
`
`Supporting Document 23
`Resubmission/Class 1
`
`Submit Date: 11/30/2011 - FDA Received Date: 11/30/2011
`
`Class 1 resubmission of NDA 201281, linagliptin plus metformin HCl FDC tablets. The
`resubmission addresses CMC issues in the original NDA review. No nonclinical data
`were included in the resubmission. The pharmacology/toxicology approval
`recommendation and labeling recommendations from the original NDA review remain
`unchanged.
`
`Retorance ID: 3077975
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

` Wm...
`This- is a re resentation of an electronic record that was signed
`egectronica ly and this page is the manifestation of the electronic
`3 gnature.
` umnmmm
`
`ls/
`----------------------------------------------------
`
`DAVID B CARLSON
`
`01/26/201 2
`
`Pharmtox approval recommendation (unchanged from original NDA review recommendation)
`
`TODD M BOURCIER
`
`01/26/2012
`
`Reference lD: 3077975
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Food and Drug Administration
`
`PHARMACOLOGY/TOXICOLOGY
`MEMO TO FILE
`
`Memorandum
`
`Date: 15 November, 2011
`NDA # 201280
`201281
`Sponsor: Boehringer Ingelheim
`Tradjenta® (Linagliptin)
`Jentadueto® (Linagliptin +
`Metformin FDC)
`Reviewer: David B. Carlson, Ph.D.
`
`Drug:
`
`Boehringer Ingelheim’s drug linagliptin, a DPP4 inhibitor, was recently reviewed for treatment
`of type 2 diabetes mellitus as both a monotherapy and a fixed dose combination with metformin.
`The initial pharmacology/toxicology reviews of rabbit embryofetal development studies were
`completed during the IND phase and results were further reviewed and summarized in the NDA
`reviews. During the course of labeling discussions it became apparent that the
`pharmacology/toxicology reviews for NDA 201280 and NDA 201281 inadvertently listed an
`incorrect rabbit strain. This memo serves as an amendment to the original
`pharmacology/toxicology reviews to clarify that Himalayan rabbits, not New Zealand White
`rabbits, were used in the pivotal embryofetal development studies with linagliptin.
`
`Reference ID: 3044773
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`DAVID B CARLSON
`11/15/2011
`Correction regarding rabbit strain -- no change in pharmtox conclusions or recommendations
`
`TODD M BOURCIER
`11/16/2011
`Correction memo
`
`Reference ID: 3044773
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number: 201281
`
`Supporting document/s: Original submission (and updates)
`Applicant’s letter date
`(CDER Stamp Date): 19 January, 2011 (1/19/11)
`Product: Linagliptin + metformin HCl FDC tablet
`
`Indication: Type 2 Diabetes Mellitus treatment
`
`Applicant: Boehringer Ingelheim Pharmaceuticals, Inc.
`
`Review Division: Metabolism and Endocrinology Products
`
`Reviewer: David B. Carlson, Ph.D.
`
`Supervisor/Team Leader: Todd Bourcier, Ph.D.
`Division Director /
`Mary Parks, M.D.
`Deputy Director:
`Eric Colman, M.D.
`Project Manager: Mehreen Hai, Ph.D.
`
`Review Completion Date: 30 September, 2011
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 201281 are owned by Boehringer Ingelheim
`Pharmaceuticals Inc. (BIPI) or are data for which BIPI has obtained a written right of
`reference. Any information or data necessary for approval of NDA 201281 that BIPI
`does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug,
`as described in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`201281.
`
`
`Reference ID: 3024468
`
`1
`
`(b) (4)
`
`

`

`
`
`Review Notes and Abbreviations/Key
`Some of the sponsor’s tables and figures from the electronic NDA submission have
`been included and cited in this review. All drug-related trends are discussed in relation
`to concurrent vehicle control groups in each study unless otherwise noted. Drugs were
`administered by oral gavage suspension in 0.5% hydroxyethylcellulose (Natrosol® 250
`HX) unless otherwise noted. Common animal strains were used and abbreviated by
`common animal name, unless noted, as follows: Wistar Han rat, CD-1 mouse, Beagle
`dog, Cynomolgus monkey, New Zealand White rabbit. Results and conclusions of some
`studies previously reviewed by this reviewer under NDA 201280 are cited and
`summarized in this NDA review.
`
`Key: Linagliptin (lina., BI 1356); metformin HCl (metformin, met.); Dipeptidyl
`peptidases – DPP4 (aka DPP-4), DPP2, DPP8, DPP9; type 2 diabetes mellitus
`(T2DM); USP (United States Pharmacopeia); NF (National Formulary); Dosing
`groups – LD (low dose), MD (mid dose), HD (high dose); mg/kg (mg/kg/day);
`once daily dosing (QD), twice daily dosing (BID); MRHD (maximum
`recommended human dose); NOAEL (no observed adverse effect level); LOAEL
`(lowest observed adverse effect level); statistically significant (ss); not statistically
`significant (nss); PD (pharmacodynamic), PK (pharmacokinetic), TK
`(toxicokinetic); BW (body weight); AUC (integrated ‘area under the curve’); GD
`(gestation day); LD (lactation day); central nervous system (CNS), peripheral
`nervous system (PNS); OGTT (oral glucose tolerance test); LFT (liver function
`test).
`
`
`
`
`Reference ID: 3024468
`
`2
`
`

`

`NDA # 201-281
`
`
`
`
`Reviewer: David B. Carlson, Ph.D.
`
`
`TABLE OF CONTENTS.................................................................................................. 3
`
`TABLE OF CONTENTS
`
`TABLE OF TABLES....................................................................................................... 5
`
`TABLE OF FIGURES ..................................................................................................... 6
`
`1 EXECUTIVE SUMMARY ......................................................................................... 7
`1.1
`INTRODUCTION.................................................................................................... 7
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 7
`1.3 RECOMMENDATIONS.......................................................................................... 11
`1.3.1 Approvability............................................................................................................11
`1.3.2 Additional Non Clinical Recommendations .............................................................11
`1.3.3 Labeling...................................................................................................................11
`2 DRUG INFORMATION .......................................................................................... 13
`2.1 DRUG............................................................................................................... 13
`2.2 RELEVANT IND/S, NDA/S, AND DMF/S ............................................................... 14
`2.2 DRUG FORMULATION ......................................................................................... 14
`2.4 Comments on Novel Excipients ...................................................................... 16
`2.5 Comments on Impurities/Degradants of Concern ........................................... 16
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.................... 17
`
`2.7 REGULATORY BACKGROUND ....................................................................... 18
`
`3 STUDIES SUBMITTED.......................................................................................... 19
`
`3.1
`
`3.2
`
`3.3
`
`STUDIES REVIEWED........................................................................................ 19
`
`STUDIES NOT REVIEWED ............................................................................... 19
`
`PREVIOUS REVIEWS REFERENCED.............................................................. 19
`
`4 PHARMACOLOGY................................................................................................ 20
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 20
`Combination linagliptin + metformin in diabetic db/db mouse – Glucose tolerance 20
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 22
`5.1
`PK/ADME........................................................................................................ 22
`6 GENERAL TOXICOLOGY..................................................................................... 24
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 24
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 24
`Dose-ranging metformin – 2-Week rat ....................................................................24
`Dose-ranging linagliptin + metformin – 2-Week rat (high dose) ..............................25
`Dose-ranging linagliptin + metformin – 2-Week rat (low dose)................................26
`
`Reference ID: 3024468
`
`3
`
`

`

`NDA # 201-281
`
`Reviewer: David B. Carlson, Ph.D.
`
`Subchronic 13—Week linagliptin + metformin in rat .................................................. 27
`
`7
`
`GENETIC TOXICOLOGY ...................................................................................... 44
`
`7.4
`
`OTHER GENETIC TOXICITY STUDIES ............................................................ 44
`
`"M" Ames assay............................................................................................ 47
`“M" Chromosome aberration assay .............................................................. 50
`
`CARCINOGENICITY ............................................................................................. 53
`
`REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 53
`
`8
`
`9
`
`9.2
`
`EMBRYONIC FETAL DEVELOPMENT ..................................................................... 53
`
`Metformin embryofetal development in rat (Seg 2 Rat) ........................................... 53
`Linagliptin + metformin embryofetal development in rat (Seg 2 Rat) ...................... 63
`
`11
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION ................................. 77
`
`Reference ID: 3024468
`
`4
`
`

`

`NDA # 201-281
`
`
`
`
`Reviewer: David B. Carlson, Ph.D.
`
`Table of Tables
`
`Table 1 – Drug product composition.............................................................................. 15
`Table 2 – Impurities....................................................................................................... 17
`Table 3 – 13-Week rat linagliptin + metformin TK summary.......................................... 43
`
`
`Reference ID: 3024468
`
`5
`
`

`

`NDA # 201-281
`
`
`
`
`Reviewer: David B. Carlson, Ph.D.
`
`Table of Figures
`
`Figure 1 – Oral glucose tolerance test in diabetic mice................................................. 20
`Figure 2 – Glucose excursion after OGTT in diabetic mice ........................................... 21
`
`
`Reference ID: 3024468
`
`6
`
`

`

`NDA # 201-281
`
`
`
`
`Reviewer: David B. Carlson, Ph.D.
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`
`The proposed linagliptin plus metformin fixed-dose combination, film-coated tablet was
`submitted in accordance with 21 USC 505(b)(2) for treatment of type 2 diabetes mellitus
`as an adjunct to diet and exercise. Both drugs are approved for use as monotherapy
`agents and linagliptin monotherapy is expected to be used in patients with inadequate
`blood sugar control on a background of metformin treatment. Boehringer Ingelheim
`owns linagliptin and submitted a written ‘right of reference’ for metformin manufactured
`by
` pertaining to the listed Glucophage® tablets. Several new
`nonclinical studies were conducted with linagliptin and metformin coadministration to
`support development of FDC clinical use. Consistent with standard practice, nonclinical
`studies assessed combination treatment of the drug substances but the exact FDC drug
`product was not assessed in animals. All pivotal studies with linagliptin were conducted
`in compliance with current GLP standards.
`
`1.2 Brief Discussion of Nonclinical Findings
`
`All pivotal nonclinical studies were conducted using oral administration of drug, which is
`the clinical exposure route, and in accordance with US FDA GLP regulations
`(21CFR58) as stated by Sponsor and confirmed by this reviewer1. Toxicity studies in
`healthy, non-diabetic animals were sufficient to identify NOAEL exposures for
`comparison to clinical exposure.
`
`Safety margins to expected human exposure were estimated using linagliptin AUC0-24 =
`158 nM*h and metformin AUC0-24 = 159 (cid:541)M*h plasma exposure in diabetic subjects at
`the proposed maximum recommended human doses (MRHD) of 2.5 mg linagliptin plus
`1000 mg metformin BID. The proposed clinical FDC doses range from 1:200 to 1:400
`linagliptin:metformin. Doses in the nonclinical studies used similar ratios to estimate
`minimum and maximum clinical ratios. Nonclinical dose ratios were considered
`acceptable based on proposed clinical uses but it is important to note that animal dosing
`was not expected to achieve maximum tolerated doses (MTD) of each drug. No toxicity
`was expected from linagliptin alone because doses were well below NOAELs identified
`in previously reviewed toxicity studies (under NDA 201280). Metformin-mediated toxicity
`was expected to limit the maximum nonclinical doses and study designs were expected
`to allow assessment of potential supra-additive or synergistic effects of combination
`linagliptin and metformin treatment.
`
`Linagliptin and metformin have distinct, complementary mechanisms of action which
`lead to improved glucose metabolism compared to monotherapy. Linagliptin inhibits the
`
`1 Pivotal studies were conducted in accordance with OECD and/or member states GLP
`principles, which are acceptable under US agreements
`
`Reference ID: 3024468
`
`7
`
`(b) (4)
`
`

`

`
`
`Reviewer: David B. Carlson, Ph.D.
`
`NDA # 201-281
`
`DPP4 enzyme, which prevents DPP4-mediated cleavage of endocrine active substrates
`including gut incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent
`insulinotropic peptide (GIP). The incretins, in combination but with GLP-1 playing a key
`role, increase insulin secretion, enhance insulin receptor sensitivity, and decrease
`hepatic glucose, gastric emptying, and food intake. DPP4 inhibition prevents the natural
`rapid breakdown of GLP-1 and GIP after their postprandial expression. Metformin
`pharmacology is still not entirely understood but it seems to improve insulin sensitivity at
`peripheral target tissues including liver, muscle, and adipose. Metformin does not seem
`to directly affect insulin production or metabolism, but treatment increases glucose
`uptake and utilization in peripheral tissues, decreases hepatic glucose production, and
`decreases intestinal glucose absorption.
`
` A
`
` single, ‘proof of concept’ study in diabetic mice showed a slight improvement in
`baseline fasting glucose and improved glucose excursion after oral glucose tolerance
`test (OGTT) with combined linagliptin and metformin treatment compared to either drug
`alone. The study was limited to one week duration and the Sponsor did not conduct a
`more robust in vivo assessment of glucose metabolism such as HbA1c after 13-week
`treatment. Nevertheless, the diabetic mouse study supports the clinical finding of
`improved blood glucose control with combined linagliptin plus metformin treatment over
`monotherapy treatments.
`
`Linagliptin monotherapy is listed for once daily dosing while metformin is given twice
`daily. The proposed FDC tablet is designed for BID dosing, thus linagliptin dosing will
`differ from the current monotherapy dosing. Total linagliptin exposure measured as
`AUC0-24 h has been shown to be similar while maximum plasma exposure, Cmax, will be
`lower clinically. Linagliptin plasma levels after 2.5 mg linagliptin BID dosing have been
`shown to be sufficient for clinical DPP4 inhibition and no effect on efficacy is expected
`with the FDC tablet BID dosing. Nonclinical studies did not identify any efficacy or safety
`endpoints that may be affected by a change from QD to BID dosing of linagliptin.
`
`Pivotal toxicity studies were conducted to bridge potential toxicity of combination
`treatment of linagliptin and metformin. No unexpected toxicity or significant supra-
`additive or synergistic interactions attributed to combination treatment were identified
`that would alter previous pharmacology and toxicology conclusions about the safe use
`of linagliptin and metformin in the treatment of type 2 diabetes. Toxicity in nonclinical
`studies was driven by metformin, as expected based on dosing ratios and large safety
`margins with linagliptin. Major target organs of metformin were heart and liver, as
`evidenced by heart hypertrophy with immune cell infiltration/inflammation and liver
`hypertrophy with concomitant hepatic injury and elevated LFT biomarkers, starting at
`approximately 10-times the expected clinical AUC exposures. Linagliptin
`coadministration did not have any apparent effect on heart, liver or other metformin-
`related toxicity on target organs including stomach and GI tract, salivary glands,
`lymphoreticular tissues, or reproductive tissues.
`
`Metformin clinical toxicity hallmarks include lactic acidosis and gastrointestinal side
`effects (e.g., diarrhea, bloating, discomfort). Based on nonclinical toxicity findings,
`
`Reference ID: 3024468
`
`8
`
`

`

`
`
`Reviewer: David B. Carlson, Ph.D.
`
`NDA # 201-281
`
`linagliptin is not expected to exacerbate potential metformin-induced metabolic acidosis
`or GI-related toxicity. No evidence of metabolic acidosis or GI distress were seen
`nonclinically with linagliptin alone at exposures exceeding 50-times human exposures.
`
`No carcinogenicity studies were conducted with the linagliptin and metformin
`combination. Neither linagliptin nor metformin are genotoxic and neither are considered
`to pose a significant carcinogenic risk at clinical exposures. Several linagliptin
`impurities, including potential or theoretical impurities and degradants, were identified
`and adequately qualified to show no significant toxicologic or carcinogenic risk. No
`further carcinogenicity testing with the combined drugs is necessary.
`
` A
`
` notable new toxicity issue was identified in the nonclinical program suggesting
`potential metformin-induced teratogenicity. Metformin is not listed as teratogenic at
`approximate clinical exposures (body surface area estimates) on current labels. Studies
`conducted by BI clearly demonstrated that metformin at 10- to 20-times human
`exposure caused skeletal malformations in Wistar Han rats. The studies confirmed that
`metformin is not teratogenic at approximate clinical exposures (clear NOAELs were
`established). Linagliptin combination treatment did not have any remarkable effect on
`the metformin-related malformations. The use of Wistar Han rats seems significant
`because most embryofetal development studies are conducted in Sprague Dawley (SD)
`rats. The reference Glucophage® label does not note the rat strain used but it seems
`clear from the original pharmacology/toxicology review(s) that SD rats were used.
`Wistar rats are reported to be more sensitive to heart malformations than SD rats2 and
`they seem to be more susceptible to the rib and scapula malformations seen with
`metformin treatment3. More importantly, metformin was clearly toxic to pregnant rats at
`the teratogenic doses, causing reduced body weight gain, modestly reduced plasma
`glucose (albeit not to marked hypoglycemic levels), and signs of metabolic acidosis.
`Body weight decrements typically cause developmental delays (e.g., delayed skeletal
`ossification), but even maternal body weight loss does not seem to cause fetal
`malformations in rats. On the other hand, both hypoglycemia and metabolic acidosis are
`known to cause fetal malformations. Importantly, data from other DPP4 inhibitor
`development programs do not confirm metformin-induced skeletal malformations.
`Several important trends were apparent from those recent studies: all were conducted
`in SD rats; all confirmed the absence of metformin teratogenicity at clinical exposures;
`all confirmed the absence of a significant effect of DPP4 inhibitor plus metformin
`combination treatment on embryofetal development; and, some of the studies confirmed
`metformin was not teratogenic at exposures up to approximately 10X MRHD.
`
`The mechanism of metformin-induced teratogenicity was not investigated. Clearly there
`are differences in the embryofetal study results for this NDA compared to those
`described on the existing metformin labels and in other DPP4 inhibitor nonclinical
`programs. It is likely the maternal toxicity at teratogenic doses contributed to fetal
`findings, since there were no fetal malformations in the absence of metformin-induced
`
`
`2 Fujino H et al. 2005. Congenital Anomalies. 45:52-58
`3 Wilby OK et al. 2007. Reproductive Toxicology 24:57(abstract)
`
`Reference ID: 3024468
`
`9
`
`

`

`
`
`Reviewer: David B. Carlson, Ph.D.
`
`NDA # 201-281
`
`maternal toxicity. It is equally important to emphasize that both metformin alone and the
`combined linagliptin plus metformin treatment were not teratogenic at approximate
`clinical exposures (by AUC), consistent with the current metformin label. Nevertheless,
`the teratogenicity findings at maternally toxic metformin doses in Wistar Han rats should
`be noted in the label for the proposed linagliptin plus metformin FDC tablets.
`
`Summary of nonclinical issues relevant to clinical use of linagliptin or the combination
`with metformin:
`
`
`
`
`
`
`
`
`1. Metformin caused fetal skeletal malformations in Wistar Han rats at maternally
`toxic doses, at approximately 10-times and higher the expected clinical exposure.
`Neither metformin alone nor combined with linagliptin was teratogenic at
`approximate clinical exposures. Linagliptin and metformin cross the placenta and
`are secreted in milk in rats. Exposure to linagliptin and metformin in nursing
`infants may present a risk of hypoglycemia.
`
`2. Hypersensitivity / pseudoallergy may occur in susceptible individuals in the
`clinical population based on linagliptin findings in dogs and minipigs. The
`evidence suggests that this reflects a histamine-related response rather than an
`immunoglobulin-mediated allergic response. This reaction is distinct from the
`ulcerative necrotic skin lesions associated with some members of the DPP4
`inhibitor class. Linagliptin did not cause necrotic skin lesions in any species in the
`non-clinical program. There is no indication that the addition of metformin
`changes this adverse response to linagliptin.
`
`3. Since DPP4 cleaves substrates other than the targeted incretin hormones,
`inhibition of DPP4 may have unintended consequences with prolonged dosing
`that were not evident in the nonclinical program. As noted in the Januvia review
`“Effects on human immunity, specifically recall responses to antigens and
`immune cell trafficking, may be adversely affected by DPP4 inhibition. This risk is
`an unavoidable characteristic of…the drug class.” Addition of metformin would
`not change the primary pharmacology of linagliptin.
`
`4. Pancreatitis has arisen as a safety concern for GLP1 targeted therapeutics,
`including the DPP4 inhibitors. Linagliptin has not caused histological changes in
`the pancreas of animals indicative of pancreatitis or pancreatic injury after long-
`term exposure to very high doses of drug. A limitation to extrapolating these
`studies to the intended diabetic clinical population is that toxicity studies are
`conducted in normoglycemic healthy animals. The combination toxicity study did
`not uncover evidence of pancreatic injury with either drug separately or
`combined.
`
`Reference ID: 3024468
`
`10
`
`

`

`NDA # 201 -281
`
`Reviewer: David B. Carlson, Ph.D.
`
`1 .3 Recommendations
`
`1.3.1 Approvability
`
`Nonclinical data support me safe use of linagliptin plus metfonnin FDC tablets under the
`proposed uses. The phannacologyltoxicology reviewer recommends approval.
`
`1.3.2 Additional Non Clinical Recommendations
`
`No additional nonclinical studies are needed.
`
`1.3.3 Labeling
`
`Specific labeling recommendations are shown below, based on the updated proposed
`label submitted by Bl. Recommended reviewer changes are shown in bold type and
`double strikethrough (i.e., strikethrough) and consistent with recommended updates to
`the Glucophage® label.
`
`8.1 Pregnangr
`Pregnancy Category C is recommended for the combination. While neither metformin
`nor the linagliptin plus metfonnin combination were teratogenic at clinical exposures, the
`current Pregnancy Category B label is not supported by the teratogenic findings in
`Wistar Han rats. It is possible a Category B label can be supported by existing
`“adequate and well-controlled studies in pregnant women” that failed to demonstrate a
`risk to the fetus, but CFR language does not support a Category B label
`recommendation by the phanntox reviewer in light of the skeletal malformations in
`Wistar Han rats.
`
`Metformin H drochlon'de
`
`Linagliptin
`Bl’s Iangua e is generall acce table, with minor modifications recommended as
`
`
`
`
`Reference ID: 3024468
`
`11
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`

`

`NDA # 201-281
`
`
`
`
`Reviewer: David B. Carlson, Ph.D.
`
`Metformin administered to female Sprague Dawley rats from gestation day 6 to
`lactation day 21 up to 600 mg/kg/day (about 2 times the maximum clinical dose
`based on body surface area comparisons) had no effect on prenatal or postnatal
`development of offspring.
`
`Metformin crosses the placenta into the fetus in rats and humans4.
`
`13 NONCLINICAL TOXICOLOGY
`BI’s language for the FDC combination is acceptable and other language accurately
`represents the approved linagliptin and Glucophage® labels. A minor change is
`recommended by pharmtox, in order to separate fertility findings from genetic toxicity.
`
`Metformin Hydrochloride
`“There was no evidence of a mutagenic potential of metformin in the following in vitro
`tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or
`chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse
`micronucleus test were also negative. [note – paragraph break inserted]
`
`Fertility of male or female rats was unaffected by metformin when administered at doses
`as high as 600 mg/kg/day, which is approximately 2 times to MRHD based on body
`surface area.”
`
`
`4 Vanky E et al. 2005. Fertil Steril 83:1575-1578.
`
`Reference ID: 3024468
`
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`
`(b) (4)
`
`(b
`)
`(4)
`
`

`

`
`
`Reviewer: David B. Carlson, Ph.D.
`
`NDA # 201-281
`
`
`2 Drug Information
`
`2.1 Drug
`
`2.1.1 CAS Registry Number
`
`Linagliptin – 668270-12-0
`Metformin HCl – 115-70-4; metformin (free base) 657-24-9
`
`2.1.2 Generic Name
`
`Linagliptin and metformin hydrochloride.
`
`2.1.3 Code Name
`
`Linagliptin – BI 1356 BS; BI 1356
`
`2.1.4 Chemical Name
`
`Linagliptin – 1H-purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-
`dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-
`Metformin HCl – 1,1-dimethylbiguanide hydrochloride;
`N,N-Dimethylimidodicarbonimidic diamide hydrochloride
`
`2.1.5 Molecular Formula/Molecular Weight
`
`Linagliptin – C25H28N8O2 / 472.54 g/mol
`Metformin HCl – C4H12ClN5 / 165.62 g/mol
`
`2.1.6 Structure (or Biochemical Description)
`
`Linagliptin –
`
`
`
`13
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`Reference ID: 3024468
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`

`NDA # 201-281
`
`Metformin HCl –
`
`
`
`Reviewer: David B. Carlson, Ph.D.
`
`
`
`
`
`2.1.7 Pharmacologic class
`
`Dipeptidyl peptidase IV (DPP4) inhibitor plus biguanide.
`
`2.2 Relevant IND/s, NDA/s, and DMF/s
`
`Linagliptin – IND 105,055 (linagliptin + metformin FDC); NDA 201280 (Tradjenta™,
`linagliptin monotherapy); IND 70,963 (linagliptin); IND 108,288 (linagliptin +
`pioglitazone); IND 108,388 (linagliptin + BI10773)
` (metformin
`Metformin – NDA 20-357 (metformin monotherapy); DMF
`hydrochloride;
` Draft labeling references Glucophage® (metformin
`hydrochloride) tablets
`DPP4 Inhibitor NDAs – NDA 21-995 (sitagliptin, Januvia®) and NDA 22-044 (sitagliptin
`+ metformin, Janumet®);
` NDA 22-350 (saxagliptin,
`Onglyza®) and NDA 200678 (saxagliptin + metformin, Kombiglyze XR ®); NDA
`22-271 (alogliptin) and NDA 22-426 (alogliptin + pioglitazone)
`
`2.2 Drug Formulation
`
`Linagliptin and metformin hydrochloride FDC tablets are proposed in three dosage
`strengths of 2.5/500, 2.5/850, 2.5/1000 mg linagliptin/mg metformin.
`
`Individual drug substances linagliptin and metformin are listed for use under the same
`manufacturing conditions for the proposed FDC formulation. No novel interactions
`between drug substances or unacceptable levels of combined impurities or residual
`solvents were identified. The current pharmacology/toxicology review is limited to the
`new FDC tablet drug product formulation.
`
`All excipients in the drug product are compendial or previously reviewed for the
`individual listed drugs (listed in Table 1). All of the individual inactive ingredients except
`arginine, including food-grade pigments, have been previously included at higher
`concentrations in oral drugs. Arginine is a common amino acid synthesized in humans
`and also consumed in food. Arginine is utilized in protein production and routinely
`metabolized and recycled through normal cellular processes. Arginine has been
`approved for iv injection directly into blood at up to 88% in solution, further supporting
`the absence of toxicity expected from systemic exposure from a drug. Thus, humans
`are normally exposed to arginine orally and systemically and drug-related oral exposure
`poses no known or unique risks at levels proposed in the FDC tablet.
`
`Reference ID: 3024468
`
`14
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 201-281
`
`Reviewer: David B. Carlson, Ph.D.
`
`No residual solvents are listed in the drui iroduct specification_
`
`Table 1 — Drug product composition
`
`linagliptin / metformin hydrochloride
`
`Ingredient
`
`Linalitin
`Metformin
`h drochloride
`
`—
`
`.
`
`_
`
`_
`
`500 m
`
`[mg/
`tablet
`
`2.50
`
`O
`
`500-000
`
`2.5 mg /
`850 m ;
`
`[mg/
`tablet
`
`2.5 mg/
`1000 m_
`
`[mg/
`tablet
`
`2.500
`
`2.500
`
`850.000
`
`1000.000
`
`Corn starch
`
`— .
`
`Co .ovidone
`—
`Colloidal silicon
`dioxide
`
`Ma y esium stearate
`
`Titanium dioxide
`
`Yellow ferric oxide
`Red ferric oxide
`
`———I
`
`Total weight
`
`Pro .
`
`lene 1 col
`n
`H promellose
`Talc
`
`Reference ID: 3024468
`
`1 5
`
`

`

`NDA # 201-281
`
`Reviewer: David B. Carlson, Ph.D.
`
`2.4
`
`Comments on Novel Excipients
`
`None. All excipients are compendial or have been previously approved in listed drug
`products.
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`Several actual and potential impurities and degradants were identified in the linagliptin
`drug substance and drug product. All of the compounds of concern were qualified in
`accordance with current guidance and none were considered to pose a significant
`toxicologic risk in the original linagliptin reviews. The Sponsor identified three impurities
`of linagliptin
`“’0
`cm
`Two of the impurities,
`were identified, qualified, and reviewed during the
`M" potential impurity was not previously identifigdo
`
`(potential degradant) and
`original linagliptin review. The
`
`“m
`
`any structural alerts for genotoxicity
`
`did not have
`(5X4)
`
`(”(0
`
`No specification is listed for
`because it is only considered a potential impurity and it was not identified in the
`absence of stress storage conditions. No further qualification of
`“m was
`considered necessary based on the absence of any genotoxic structural alert or other
`predicted toxicity, consistent with ICH guideliness.
`m" specified at
`"m as a
`degradant in the drug product, was tested for potential genetic toxicity in vitro and found
`to be negative for mutagenic and clastogenic genotoxic potential.
`“M" was al