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

`

`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: 208026
`Supporting document/s: SDN-1
`Applicant’s letter date
`(CDER Stamp Date): July 27, 2015
`Product: Linagliptin/metformin XR FDC
`Indication: Type 2 diabetes mellitus
`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: Jean-Marc Guettier, M.D.
`Project Manager: Richard Whitehead, M.S.
`Review Completion Date: 4/20/16
`Disclaimer
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 208026 are owned by Boehringer Ingelheim or are data
`for which Boehringer Ingelheim has obtained a written right of reference. Any
`information or data necessary for approval of NDA 208026 that Boehringer Ingelheim
`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
`208026.
`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.
`
`Key: Linagliptin (LINA); Metformin HCl extended release (metformin XR, aka metformin ER);
`fixed-dose combination (FDC), once daily dosing (QD); mg/kg (mg/kg/day); MRHD
`(maximum recommended human dose); IR (immediate release), XR (extended release);
`polyethylene oxide (PEO), polyethylene glycol (PEG); molecular weight (MW)
`
`Reference ID: 3925784
`
`1
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS...................................................................................................2
`TABLE OF TABLES ........................................................................................................3
`TABLE OF FIGURES.......................................................................................................4
`1
`EXECUTIVE SUMMARY...........................................................................................5
`1.1
`INTRODUCTION .....................................................................................................5
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................5
`1.3
`RECOMMENDATIONS .............................................................................................7
`1.3.1
`Approvability...........................................................................................................................................7
`1.3.2
`Additional Non Clinical Recommendations............................................................................................7
`1.3.3
`Labeling ..................................................................................................................................................7
`2 DRUG INFORMATION..............................................................................................8
`2.1
`DRUG ..................................................................................................................8
`2.2
`RELEVANT IND/S, NDA/S, AND DMF/S ..................................................................9
`2.2
`DRUG FORMULATION ............................................................................................9
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ....................15
`2.7
`REGULATORY BACKGROUND ........................................................................15
`3
`STUDIES SUBMITTED...........................................................................................15
`3.1
`STUDIES REVIEWED .........................................................................................15
`3.3
`PREVIOUS REVIEWS REFERENCED...............................................................15
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION..................................16
`
`Reference ID: 3925784
`
`2
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`Table of Tables
`
`Table 1 – Key drug product information ...........................................................................9
`Table 2 – Drug Product Composition..............................................................................11
`Table 3 –
`Coating
` Composition.............................................14
`
`Reference ID: 3925784
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`Figure 1 – FDC Coated Tablet (Schematic) ...................................................................10
`
`Table of Figures
`
`Reference ID: 3925784
`
`4
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`
`Boehringer Ingelheim (Bl) submitted NDA 208026 for a combination of two approved
`drugs, linagliptin and metformin extended release (metformin XR), in fixed-dose
`combination (FDC) tablets to be given once daily (QD) to treat type 2 diabetes mellitus.
`Bl owns linagliptin (NDA 201280) and linagliptin plus metformin immediate release
`(metformin IR) FDC tablets (NDA 201281) and cites a complete ‘right of reference’ to all
`information supporting the metformin extended release (metformin XR) drug substance
`and drug product information under NDA 21748 (GLUMETZA®). Nonclinical support for
`the safety of the proposed FDC tablets is claimed from cross-referencing information in
`the approved drug products. Clinical studies supporting the new FDC drug product were
`limited to Phase I, bioequivalence trials in healthy men and women.
`
`1.2
`
`Brief Discussion of Nonclinical Findings
`
`No new nonclinical information was submitted to support the proposed linagliptin and
`metformin XR FDC tablets. The Sponsor relied entirely on cross-referenced nonclinical
`data from previously approved monotherapy drugs (linagliptin, metformin XR) and
`linagliptin plus metformin IR FDC. The drug substances in the proposed FDC tablets are
`identical to those previously approved. Cross-referenced extended release metformin is
`marketed as GLUMETZA® and the metformin drug substance is identical to that in the
`proposed drug product. A slight formulation modification is proposed for the extended
`release drug product compared to the referenced drug product. Clinical bioequivalence
`of the drug substances in the current formulation were confirmed and human exposures
`at the maximum recommended human dose (MRHD) are consistent with exposure to
`individual drug substances — AUCM,"I = 158 nM*h linagliptin (5 mg OD) and AUC0_24h =
`159 pM*h metformin XR (1000 mg QD).
`
`There are no existing or new pharmacology or toxicology concerns about the listed drug
`substances proposed in the new FDC drug product. The pivotal nonclinical issues in the
`proposed drug product are
`"M compared to referenced metformin
`XR and
`"M"
`
`Sponsor stated that no novel excipients were used in the drug product formulation and
`that no new impurities, degradation products,
`“M" were identified.
`
`The
`
`Nonclinical review of the drug product excipients and specifications independently
`verified that there are no new excipients or impurities in the proposed drug product. The
`polyethylene oxide used in the drug product,
`M"
`
`Reference ID: 3925784
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`(ll) (4)
`
`PEGs and PEOs are marketed
`
`over-the-counter (OTC; i.e., without a prescription) as laxatives. The OTC laxatives are
`typically in the range of
`"M" glmol with recommended dosage of approximately 2'3
`g/day. No absorption or systemic toxicity are predicted from the
`glmol PEOs in the listed and proposed metformin XR formulations
`compared to the OTC laxatives. Laxative effects are not expected from the
`approximately "“9 mg/day PEO excipient exposures,
`than OTC laxatives. Any potential laxative effects for the XR tablets would be
`expected to be simply a clinical tolerability issue and not a toxicity issue.
`
`(I!) (4)
`
`(b) (4)
`
`“M coating agents were used in different film-coat layers of
`Several commercial
`the drug product. The exact
`“M" formulations have not been previously used in
`listed drug products but the Sponsor provided qualitative and quantitative composition
`of the
`“M" coating agents and printing ink. A review of all components of the
`“m formulations verified their use in approved drug products in the FDA Inactive
`Ingredients Guide1 and no novel excipients were identified.
`
`Combination toxicology studies of linagliptin and metformin coadministration in rats
`were previously reviewed and cross-referenced to support the new linagliptin plus
`metformin XR drug product. No unexpected toxicity or significant supra—additive or
`synergistic interactions from combination treatment were identified. As summarized in
`the Pharmacology/Toxicology Review for NDA 201281 (linagliptin plus metformin IR
`FDC):2
`
`“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."
`
`1 US. Food and Drug Administration, Inactive Ingredient Search for Approved Drug
`Products, http://wwwaccessdata.fda.gov/scripts/cder/iig/index.Cfm
`2 Carlson DB. NDA 201281, Pharmacology/Toxicology Review, 10/4/11
`
`Reference ID: 3925784
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`Embryofetal toxicity was observed in rats treated with metformin alone and with
`linagliptin and metformin coadministration as noted in the nonclinical review for NDA
`201281. The current label for linagliptin plus metformin IR FDC (JENTADUETO®)
`includes the embryofetal rat findings and the information is maintained in the proposed
`label for this drug product. As noted in the Pharmacology/Toxicology Review for NDA
`201281 (JENTADUETO®),2
`
`“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 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.”
`
`1.3 Recommendations
`
`1.3.1 Approvability
`
`Nonclinical data (cross-referenced from approved drugs) support the safe use of
`linagliptin plus metformin extended release FDC tablets under the proposed uses. The
`pharmacology/toxicology reviewer recommends approval.
`
`1.3.2 Additional Non Clinical Recommendations
`
`No additional nonclinical studies are needed.
`
`1.3.3 Labeling
`
`No new nonclinical information was provided and no updates are necessary for
`nonclinical data described in existing labels. The Sponsor submitted proposed labeling
`updates in compliance with the ‘Pregnancy and Lactation Labeling Rule’ (PLLR). The
`proposed labeling is based on labels for linagliptin monotherapy, metformin XR
`monotherapy, and linagliptin/metformin IR FDC tablets. Labeling recommendations
`were provided directly on the Division’s shared document.
`
`Reference ID: 3925784
`
`7
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`2
`
`Drug Information
`
`2.1 Drug
`
`Jentadueto XRTM (proposed)
`Linagliptin and metformin HCl extended release (XR) FDC film coated tablets.
`
`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 / metformin HCl XR
`
`2.1.3 Code Name
`
`Linagliptin (BI 1356; BI 1356 BS)
`
`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
`
`Reference ID: 3925784
`
`8
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`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`Metformin HCI
`
`NH
`
`NH
`
`HzNJLqu'fi/Cm ’ HCI
`
`c H3
`
`2.1.7 Pharmacologic class
`
`Dipeptidyl peptidase 4 (DPP-4) inhibitor (linagliptin) I
`Biguanide (metformin HCI)
`
`2.2 Relevant IND/s, NDA/s, and DMFIs
`
`IND
`IND
`
`M14)
`
`(3)“)
`
`NDA 201280 — Linagliptin (TRADJENTA®)
`NDA 201281 — Linagliptin/metformin HCI FDC (JENTADUETO®)
`NDA 021748 — Metformin HCI extended release (GLUMETZA®)
`
`2.2 Drug Formulation
`
`Two fixed-dose combination, film coated tablet strengths are proposed for QB dosing
`(see Sponsor‘s description in Table 1):
`
`2.5 mg linagliptin I 1000 mg metformin XR
`5 mg linagliptin / 1000 mg metformin XR
`
`Table 1 — Key drug product information
`
`Key information of linagliptin ,l metformin hydrochloride extended
`release (ER) coated tablets
`
`Name of the n
`
`.
`
`. oduct;
`
`linagliptin l" metformin hydrochloride extended release (ER) coated tablets
`
`Drug substances:
`
`Linagliptin
`Metfonnin h drochlon'de
`
`C Im .nv_
`Dosa ' fmm:
`Indicafiom
`'
`
`Boehxinger Ingelheim
`Tablets (extended release coated tablets)
`Adult patients with type 2 diabetes mellitus
`2.5 mg linagliptin + 1000 mg metformin hydrochloride
`5 m linali -'- +1000 111 metformin hvdrochloride
`
`Route of administration:
`
`A schematic of the drug product, consisting of a metformin HCI extended release core
`and an immediate release layer of linagliptin is shown in the Sponsor’s Figure 1.
`
`Reference ID: 3925784
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`Figure 1 - FDC Coated Tablet (Schematic)
`
`
`
`The Sponsor's summaries of inactive ingredients in the film coated tablets are shown in
`Table 2 and Table 3, below. The S nsor stated the drug product formulation “uses
`excipients
`, mixtures of excipients) that are
`commonly used in similar proportions in approved oral drug products. All excipients are
`compendial.” An independent analysis of the drug product formulation by this
`Pharmacology/Toxicology Reviewer confirmed that all listed exci
`ients are found in
`
`commercla ormu a Ions were provided and all compounds were oun In Slml ar oral
`products described in the IIG- Discussion of notable individual excipient—
`fonnulations are provided below.
`
`FDA’s ublic Inactive In redients Guide (IIG)3,# The individual componen
`
`3 US. Food and Drug Administration, Inactive Ingredient Search for Approved Drug
`Products, http://www.accessdata.fda.govlscripts/cderliiglindefom, accessed 4/20/16
`
`Reference ID: 3925784
`
`1 0
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`Table 2 — Drug Product Composition
`
`Qnafiufive and Quantitative Composition of Linaglipun/Metfounh
`HCl ERCooted Tabiets, 2-5 mg/leg and 5 mgIIOOO mg
`
`
`
`Reference ID: 3925784
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`4 Carlson DB.
`
`, Pharmacology/Toxicology Memo to File, 6/14/13
`
`Reference ID: 3925784
`
`12
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`
`
`
`The manufacturer stated that all excipients and colors in the— formulations used
`in the linagli tinlmetfonnin XR tablets are com endial and reVIous a
`roved for
`
`human use.
`
`
`e ponsor
`I
`prOVl e
`
`
`e qua I a we an quan I a we compOSI Ion 0
`color used, which are
`shown in Table 3.
`
`The individual components were verified by this Pharmacology/1'oxicolo Reviewer to
`
`be resent in similar
`in the IIG. Table 3 notes the
`
`
`
`
`rintin ink and the total amount listed in the drug product (Table 2) is— Thus,
`# of ink used to label the a
`roximately- tablets will con aIn several
`or ers o magnitudefijnoted in the "Min ink’s formulation, does not
`present a significant ora exposure rIs , and is in facth used in oral
`
`owever,
`
`ac IS use on y as a
`
`
`
`drug products listed in the "G.
`
`Reference ID: 3925784
`
`1 3
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`litativemd woman-mum
`
`Table 3 --(mating- Composition
`
`
`
`Reference ID: 3925784
`
`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`2.4
`
`Comments on Novel Excipients
`
`The Sponsor claims that no novel excipients are used in the drug product. All excipients
`listed in the drug product information are compendial and controls according to the
`current compendial monograph for each excipient as noted by the Sponsor in their
`submission.
`
`M" coating agents and printing inks used in
`The Sponsor stated that
`the drug product are non-compendial commercial excipient mixtures that meet
`regulatory and compendial requirements for their intended use.
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`Drug substances are identical to those previously approved and sourced from the same
`manufacturing sites as the approved products. Impurities and degradants in the
`approved drug substances have been qualified nonclinically and previously reviewed.5,6
`No drug product impurities or degradants of concern were noted by the Sponsor or the
`CMC/Quality Reviewer. The Sponsor stated that specifications comply with ICH Q6.
`This Pharmacology/Toxicology Reviewer did not identify any impurity concerns based
`on a review of the drug product specifications.
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`2.7 Regulatory Background
`
`This is the original submission for linagliptin/metformin XR tablets. All drug substances
`have been previously approved and the Sponsor owns, or has a written ‘right of
`reference' to all of the drug substances and drug product components.
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`None. No pharmacology or toxicology studies submitted. All nonclinical studies
`supporting the NDA are cross-referenced from the Sponsor’s other NDAs.
`
`3.3
`
`Previous Reviews Referenced
`
`Carlson DB. NDA 201281, Pharmacology/Toxicology Review, 10/4/11.
`Carlson DB.
`“m", Pharmacology/Toxicology Memo to File, 6/14/13.
`Carlson DB.
`"m", Pharmacologyfroxicology Review #1, 3/26/13.
`
`5 Carlson DB. NDA 201281, Pharmacologyfl'oxicology Review, 10l4/11
`6 Carlson DB.
`m“) Pharmacology/Toxicology Review #1, 3/26/13
`
`Reference ID: 3925784
`
`1 5
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`

`

`NDA # 208026 (Review #1)
`
`Reviewer: David B. Carlson, Ph.D.
`
`Integrated Summary and Safety Evaluation
`11
`The proposed linagliptin/metformin XR FDC tablet NDA was submitted in accordance
`with 21 USC 505(b)(1) for treatment of type 2 diabetes mellitus. No nonclinical studies
`were submitted. An integrated summary of nonclinical information of individual drug
`substances and linagliptin/metformin immediate release coadministration studies was
`provided. The Sponsor relied on cross-referencing existing nonclinical data from several
`listed individual and FDC drugs.
`
`Pivotal nonclinical review issues were limited to potential impurities and novel
`excipients. The drug substances are identical to listed drugs and the drug product is
`only slightly modified from the listed linagliptin/metformin IR FDC and the listed
`metformin XR drug product (GLUMETZA®). The Pharmacology/Toxicology review did
`not identify any new safety concerns. No novel excipients or unqualified impurities were
`identified.
`
`Clinical bioavailability/bioequivalence studies confirmed similar pharmacokinetic profiles
`for linagliptin and metformin compared to individual drug substances and the listed
`linagliptin/metformin immediate release formulation. Pharmacology and toxicology
`studies conducted with linagliptin, metformin, and linagliptin/metformin coadministration
`support proposed use of the new extended release FDC clinical formulation.
`
`Reference ID: 3925784
`
`16
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`05/03/2016
`Nonclinical approval recommendation
`
`TODD M BOURCIER
`05/04/2016
`I concur
`
`Reference ID: 3925784
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`NDA/BLA Number: 208026 Applicant: Boehringer Ingelheim Stamp Date: 27 July, 2015
`Drug Name: linagliptin/
`NDA/BLA Type: 505(b)(1)
`metformin XR FDC
`
`On initial overview of the NDA/BLA application for filing:
`
`Content Parameter
`1 Is the pharmacology/toxicology section
`organized in accord with current regulations
`and guidelines for format and content in a
`manner to allow substantive review to
`begin?
`2 Is the pharmacology/toxicology section
`indexed and paginated in a manner allowing
`substantive review to begin?
`3 Is the pharmacology/toxicology section
`legible so that substantive review can
`begin?
`4 Are all required and requested IND studies
`in accord with 505 (b)(1) and (b)(2)
`including referenced literature) completed
`and submitted (carcinogenicity,
`mutagenicity, teratogenicity, effects on
`fertility, juvenile studies, acute and repeat
`dose adult animal studies, animal ADME
`studies, safety pharmacology, etc)?
`5 If the formulation to be marketed is
`different from the formulation used in the
`toxicology studies, have studies by the
`appropriate route been conducted with
`appropriate formulations? (For other than
`the oral route, some studies may be by
`routes different from the clinical route
`intentionally and by desire of the FDA).
`6 Does the route of administration used in the
`animal studies appear to be the same as the
`intended human exposure route? If not, has
`the applicant submitted a rationale to justify
`the alternative route?
`7 Has the applicant submitted a statement(s)
`that all of the pivotal pharm/tox studies
`have been performed in accordance with the
`GLP regulations (21 CFR 58) or an
`explanation for any significant deviations?
`8 Has the applicant submitted all special
`studies/data requested by the Division
`during pre-submission discussions?
`
`Yes No
`
`Comment
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Data required for review are incorporated
`by reference from NDAs 201280
`(linagliptin), 201281 (linagliptin/metformin
`FDC), and right of reference to NDA
`021748 (metformin XR).
`
`Extended release FDC formulation
`incorporates appropriate pharmacology/
`toxicology studies by reference.
`
`Statements of GLP compliance included in
`referenced NDAs.
`
`N/A. No special studies were requested.
`Justification of novel inactive ingredient
`was discussed with sponsor during pre-
`NDA phase and is a review issue.
`
`Reference ID: 3818636
`
`

`

`Comment
`Preliminary review of label shows
`pharmacology/toxicology sections
`incorporate language from listed drugs in
`the FDC drug product.
`
`X
`
`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`Content Parameter
`Yes No
`9 Are the proposed labeling sections relative
`to pharmacology/toxicology appropriate
`including human dose multiples expressed
`in either mg/m2 or comparative
`serum/plasma levels) and in accordance
`with 201.57?
`10 Have any impurity, degradant,
`extractable/leachable, etc. issues been
`addressed? (New toxicity studies may not
`be needed.)
`11 If this NDA/BLA is to support a Rx to OTC
`switch, have all relevant studies been
`submitted?
`12 If the applicant is entirely or in part
`supporting the safety of their product by
`relying on nonclinical information for
`which they do not have the right to the
`underlying data (i.e., a 505(b)(2) application
`referring to a previous finding of the agency
`and/or literature), have they provided a
`scientific bridge or rationale to support that
`reliance? If so, what type of bridge or
`rationale was provided (e.g., nonclinical,
`clinical PK, other)?
`N/A – not applicable
`
`N/A. No issues were previously uncovered.
`Any impurity or degradant issues in the
`formulation will be addressed in the review.
`
`N/A.
`
`N/A.
`
`IS THE PHARMACOLOGY/TOXICOLOGY SECTION OF THE APPLICATION
`FILEABLE? __Yes____
`
`No issues were identified for incorporation in the 74-day letter.
`
`Reference ID: 3818636
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`09/11/2015
`Nonclinical information supports filing
`
`TODD M BOURCIER
`09/11/2015
`I concur
`
`Reference ID: 3818636
`
`