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

`

`505(b)(2) ASSESSMENT
`
`A lication Information
`
`NDA # 201281
`
`NDA Supplement #2 N/A
`
`Efficacy Supplement Type: N/A
`
`Proprietary Name: TBD
`Established/Proper Name: Linagliptin/Metformin Hydrochloride Fixed-Dose Combination
`Dosage Form: Tablets
`Stren hs: 2.5 m_/500 m_ 2.5 m_l850 m_ 2.51n_/1000 m_
`Applicant: Boehringer Ingelheim Pharmaceuticals, Inc.
`
`Proposed Indication(s): Treatment of Type 2 Diabetes Mellitus
`
`Date of Receipt: January 19, 2011 (resubmitted on November 30, 2011 after Complete
`Reponse issued on November 16, 2011)
`
`PDUFA Goal Date:
`Januarv 30, 2012
`
`Action Goal Date (if different):
`
`GENERAL INFORMATION
`
`1)
`
`Is this application for a recombinant or biologically-derived product and/or protein or peptide
`product OR is the applicant relying on a recombinant or biologically-derived product and/or
`protein or peptide product to support approval of the proposed product?
`
`YES
`
`|:|
`
`N0|Z|
`
`If “YES “contact the (b)(.?) review staflin the Immediate Oflice, Ofiice ofNew Drugs.
`
`Reference ID: 30771 89
`
`Page 1
`Version: March 2009
`
`

`

`INFORMATION PROVIDED VIA RELIANCE
`(LISTED DRUG OR LITERATURE)
`
`2) List the information essential to the approval of the proposed drug that is provided by reliance
`on our previous finding of safety and efficacy for a listed drug or by reliance on published
`literature. (If not clearly identified by the applicant, this information can usually be derived
`from annotated labeling.)
`
`Source of information* (e.g.,
`published literature, name of
`referenced product)
`Glucophage (metformin hydrochloride)
`tablets (NDA 020357)
`
`Information provided (e.g.,
`pharmacokinetic data, or specific
`sections of labeling)
`Safety and efficacy data throughout
`US Prescribing Information
`
`Published literature
`
`Use in Specific Populations -
`Pregnancy (Section 8.1 of label)
` *each source of information should be listed on separate rows
`
`3) Reliance on information regarding another product (whether a previously approved product
`or from published literature) must be scientifically appropriate. An applicant needs to
`provide a scientific “bridge” to demonstrate the relationship of the referenced and proposed
`products. Describe how the applicant bridged the proposed product to the referenced
`product(s). (Example: BA/BE studies)
`
`BA/BE studies for Glucophage
`
`RELIANCE ON PUBLISHED LITERATURE
`
`4)
`
`(a) Regardless of whether the applicant has explicitly stated a reliance on published literature
`to support their application, is reliance on published literature necessary to support the
`approval of the proposed drug product (i.e., the application cannot be approved without the
`published literature)?
` YES
` NO
`
`If “NO,” proceed to question #5.
`
`(b) Does any of the published literature necessary to support approval identify a specific (e.g.,
`brand name) listed drug product?
` YES
` NO
`
`If “NO”, proceed to question #5.
`If “YES”, list the listed drug(s) identified by name and answer question #4(c).
`
`(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)? N/A
` YES
`
` NO
`
`
`
`
`
`Page 2
`Version: March 2009
`
`Reference ID: 3077189
`
`

`

`RELIANCE ON LISTED DRUG(S)
`
`Reliance on published literature which identifies a specific approved (listed) drug constitutes
`reliance on that listed drug. Please answer questions #5-9 accordingly.
`
`5) Regardless of whether the applicant has explicitly referenced the listed drug(s), does the
`application rely on the finding of safety and effectiveness for one or more listed drugs
`(approved drugs) to support the approval of the proposed drug product (i.e., the application
`cannot be approved without this reliance)?
`
` NO
` YES
`If “NO,” proceed to question #10.
`
`6) Name of listed drug(s) relied upon, and the NDA/ANDA #(s). Please indicate if the applicant
`explicitly identified the product as being relied upon (see note below):
`
`Name of Drug
`
`NDA/ANDA #
`
`Glucophage (metformin hydrochloride) tablets
`
`NDA 020357
`
`Did applicant
`specify reliance on
`the product? (Y/N)
`Yes
`
`Applicants should specify reliance on the 356h, in the cover letter, and/or with their patent
`certification/statement. If you believe there is reliance on a listed product that has not been
`explicitly identified as such by the applicant, please contact the (b)(2) review staff in the
`Immediate Office, Office of New Drugs.
`
`7)
`
`If this is a (b)(2) supplement to an original (b)(2) application, does the supplement rely upon
`the same listed drug(s) as the original (b)(2) application?
` N/A
` NO
`
` YES
`If this application is a (b)(2) supplement to an original (b)(1) application or not a supplemental
`application, answer “N/A”.
`If “NO”, please contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.
`
`8) Were any of the listed drug(s) relied upon for this application:
`a) Approved in a 505(b)(2) application?
` YES
` NO
`
`If “YES”, please list which drug(s).
`Name of drug(s) approved in a 505(b)(2) application:
`
`b) Approved by the DESI process?
` YES
` NO
`
`If “YES”, please list which drug(s).
`Name of drug(s) approved via the DESI process:
`
`c) Described in a monograph?
` YES
` NO
`
`If “YES”, please list which drug(s).
`
`Name of drug(s) described in a monograph:
`
`
`
`
`
`Page 3
`Version: March 2009
`
`Reference ID: 3077189
`
`

`

`d) Discontinued from marketing?
` YES
` NO
`
`If “YES”, please list which drug(s) and answer question d) i. below.
`If “NO”, proceed to question #9.
`Name of drug(s) discontinued from marketing:
`
`i) Were the products discontinued for reasons related to safety or effectiveness? N/A
` YES
`
` NO
`(Information regarding whether a drug has been discontinued from marketing for
`reasons of safety or effectiveness may be available in the Orange Book. Refer to
`section 1.11 for an explanation, and section 6.1 for the list of discontinued drugs. If
`a determination of the reason for discontinuation has not been published in the
`Federal Register (and noted in the Orange Book), you will need to research the
`archive file and/or consult with the review team. Do not rely solely on any
`statements made by the sponsor.)
`
`9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for
`example, “This application provides for a new indication, otitis media” or “This application
`provides for a change in dosage form, from capsule to solution”).
`
`This application provides for a new fixed-dose combination of linagliptin and
`metformin hydrochloride, for the treatment of type 2 diabetes.
`
`The purpose of the following two questions is to determine if there is an approved drug product
`that is equivalent or very similar to the product proposed for approval that should be referenced
`as a listed drug in the pending application.
`
`The assessment of pharmaceutical equivalence for a recombinant or biologically-derived product
`and/or protein or peptide product is complex. If you answered YES to question #1, proceed to
`question #12; if you answered NO to question #1, proceed to question #10 below.
`
`10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)
`application that is already approved (via an NDA or ANDA)?
`
`(Pharmaceutical equivalents are drug products in identical dosage forms that: (1) contain
`identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the
`same therapeutic moiety, or, in the case of modified release dosage forms that require a
`reservoir or overage or such forms as prefilled syringes where residual volume may vary,
`that deliver identical amounts of the active drug ingredient over the identical dosing period;
`(2) do not necessarily contain the same inactive ingredients; and (3) meet the identical
`compendial or other applicable standard of identity, strength, quality, and purity, including
`potency and, where applicable, content uniformity, disintegration times, and/or dissolution
`rates. (21 CFR 320.1(c)).
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`equivalent must also be a combination of the same drugs.
`
` YES
`
`
`
` NO
`
` If “NO” to (a) proceed to question #11.
`If “YES” to (a), answer (b) and (c) then proceed to question #12.
`
`
`
`
`
`Page 4
`Version: March 2009
`
`Reference ID: 3077189
`
`

`

`(b) Is the pharmaceutical equivalent approved for the same indication for which the
`505(b)(2) application is seeking approval? N/A
` YES
`
`
` NO
`
`(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent? N/A
` YES
` NO
`
`
`
`If “YES” to (c) and there are no additional pharmaceutical equivalents listed, proceed to
`question #12.
`If “NO” or if there are additional pharmaceutical equivalents that are not referenced by the
`application, list the NDA pharmaceutical equivalent(s); you do not have to individually list all
`of the products approved as ANDAs, but please note below if approved approved generics are
`listed in the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office,
`Office of New Drugs.
`
`Pharmaceutical equivalent(s): N/A
`
`11) (a) Is there a pharmaceutical alternative(s) already approved (via an NDA or ANDA)?
`
`(Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its
`precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each
`such drug product individually meets either the identical or its own respective compendial or other
`applicable standard of identity, strength, quality, and purity, including potency and, where applicable,
`content uniformity, disintegration times and/or dissolution rates. (21 CFR 320.1(d)) Different dosage
`forms and strengths within a product line by a single manufacturer are thus pharmaceutical
`alternatives, as are extended-release products when compared with immediate- or standard-release
`formulations of the same active ingredient.)
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`alternative must also be a combination of the same drugs.
`
` NO
`
` YES
`If “NO”, proceed to question #12.
`
`(b) Is the pharmaceutical alternative approved for the same indication for which the
`505(b)(2) application is seeking approval? N/A
` YES
`
` NO
`
`(c) Is the approved pharmaceutical alternative(s) referenced as the listed drug(s)? N/A
` YES
`
` NO
`
`If “YES” and there are no additional pharmaceutical alternatives listed, proceed to question
`#12.
`If “NO” or if there are additional pharmaceutical alternatives that are not referenced by the
`application, list the NDA pharmaceutical alternative(s); you do not have to individually list all
`of the products approved as ANDAs, but please note below if approved generics are listed in
`the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of
`New Drugs.
`
`Pharmaceutical alternative(s): N/A
`
`
`
`
`
`Reference ID: 3077189
`
`Page 5
`Version: March 2009
`
`

`

`PATENT CERTIFICATION/STATEMENTS
`
`12) List the patent numbers of all unexpired patents listed in the Orange Book for the listed
`drug(s) for which our finding of safety and effectiveness is relied upon to support approval of
`the (b)(2) product.
`
`Listed drug/Patent number(s): None
`
` No patents listed
`
`proceed to question #14
`
`13) Did the applicant address (with an appropriate certification or statement) all of the unexpired
`patents listed in the Orange Book for the listed drug(s) relied upon to support approval of the
`(b)(2) product?
` YES
` NO
`
`If “NO”, list which patents (and which listed drugs) were not addressed by the applicant.
`
`Listed drug/Patent number(s): N/A
`
`14) Which of the following patent certifications does the application contain? (Check all that
`apply and identify the patents to which each type of certification was made, as appropriate.)
`
` No patent certifications are required (e.g., because application is based solely on
`published literature that does not cite a specific innovator product)
`
` 21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to
`FDA. (Paragraph I certification)
`
` 21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)
`
`Patent number(s): N/A
`
` 21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph
`III certification)
`
`Patent number(s): N/A
`
`
`
`Expiry date(s): N/A
`
` 21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid, unenforceable, or will not be
`infringed by the manufacture, use, or sale of the drug product for which the
`application is submitted. (Paragraph IV certification). If Paragraph IV certification
`was submitted, proceed to question #15.
`
` 21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the
`NDA holder/patent owner (must also submit certification under 21 CFR
`314.50(i)(1)(i)(A)(4) above). If the applicant has a licensing agreement with the
`NDA holder/patent owner, proceed to question #15.
`
` 21 CFR 314.50(i)(1)(ii): No relevant patents.
`
`
`
`
`
`Page 6
`Version: March 2009
`
`Reference ID: 3077189
`
`

`

` 21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent
`and the labeling for the drug product for which the applicant is seeking approval
`does not include any indications that are covered by the use patent as described in
`the corresponding use code in the Orange Book. Applicant must provide a
`statement that the method of use patent does not claim any of the proposed
`indications. (Section viii statement)
`
`
`
`
`Patent number(s): N/A
`Method(s) of Use/Code(s):
`
`15) Complete the following checklist ONLY for applications containing Paragraph IV
`certification and/or applications in which the applicant and patent holder have a licensing
`agreement:
`
`(a) Patent number(s): N/A
`(b) Did the applicant submit a signed certification stating that the NDA holder and patent
`owner(s) were notified that this b(2) application was filed [21 CFR 314.52(b)]? N/A
` YES
`
` NO
`If “NO”, please contact the applicant and request the signed certification.
`
`(c) Did the applicant submit documentation showing that the NDA holder and patent
`owner(s) received the notification [21 CFR 314.52(e)]? This is generally provided in the
`form of a registered mail receipt. N/A
` YES
` NO
`
`If “NO”, please contact the applicant and request the documentation.
`
`(d) What is/are the date(s) on the registered mail receipt(s) (i.e., the date(s) the NDA holder
`and patent owner(s) received notification):
`
`Date(s): N/A
`
`(e) Has the applicant been sued for patent infringement within 45-days of receipt of the
`notification listed above? N/A
`
`Note that you may need to call the applicant (after 45 days of receipt of the notification)
`to verify this information UNLESS the applicant provided a written statement from the
`notified patent owner(s) that it consents to an immediate effective date of approval.
`
`YES
`
`NO
`
` Patent owner(s) consent(s) to an immediate effective date of
`approval
`
`
`
`
`
`Page 7
`Version: March 2009
`
`Reference ID: 3077189
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`MEHREEN HAI
`01/25/2012
`
`Reference ID: 3077189
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`
`****Pre-decisional Agency Information****
`
`Memorandum
`Date:
`
`November 3, 2011
`
`To:
`
`
`From:
`
`CC:
`
`
`
`
`
`
`
`
`Subject:
`
`
`
`
`
`Mehreen Hai, Regulatory Project Manager,
`Division of Metabolism and Endocrinology Products (DMEP)
`
`Samuel Skariah, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Kendra Jones, Regulatory Review Officer, OPDP
`Olga Salis, Regulatory Project Manager, OPDP
`Lisa Hubbard, Team Leader - Professional Review Group 3, OPDP
`
`NDA 201281 TRADE (linagliptin and metformin HCl) tablets
`
`OPDP labeling comments for TRADE (linagliptin and metformin HCl) tablets
`
`OPDP has reviewed the proposed Prescribing Information (PI) for TRADE accessed from the
`eRoom on 11/01/11:
`
`(http://eroom.fda.gov/eRoom/CDER3/CDERDivisionofMetabolismandEndocrinologyProductsCon
`sults/0 2561f)
`
`In addition, OPDP has reviewed the carton and container labeling submitted by the sponsor on
`01/19/11:
`
`(\\Cdsesub1\evsprod\NDA201281\201281.enx)
`
`OPDP’s comments regarding the PI are provided in the marked up version below. OPDP does
`not have any comments regarding the proposed carton and container labeling. Comments
`regarding the patient package insert (PPI) will be provided in a separate memo at a later date.
`
`Thank you for the opportunity to comment on these proposed materials.
`
`If you have any questions on the PI, please contact Sam Skariah at 301. 796. 2774 or
`Sam.Skariah@fda.hhs.gov.
`
`Reference ID: 3039406
`
`1
`
`17 pages of draft labeling has been withheld
`in full as B(4) CCI/TS immediately
`following this page
`
`

`

`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`SAMUEL M SKARIAH
`
`11/03/2011
`
`Reference ID: 3039406
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

` Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Label and Labeling Review
`
`Date:
`
`October 28, 2011
`
`Reviewer
`
`Terri Wood-Cummings, MD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`Carlos Mena-Grillasca, RPh
`Team Leader
`Division of Medication Error Prevention and Analysis
`
`Carol Holquist, RPh
`Division Director
`Division of Medication Error Prevention and Analysis
`
` (Linagliptin and Metformin Hydrochloride) Tablets
`Drug Name and Strengths
` 2.5 mg/500 mg, 2.5 mg/850 mg, and 2.5 mg/1000 mg
`
`Application Type/Number NDA 201281
`Sponsor
`Boehringer Ingelheim
`OSE RCM #:
`2011-353
`
`*** This document contains proprietary and confidential information that should not be
`released to the public.***
`
`Reference ID: 3036918
`
`(b) (4)
`
`

`

`INTRODUCTION
`1
`This review evaluates the proposed container labels and Prescribing Information labeling
`for
` (Linagliptin and Metformin) and its vulnerability to medication errors.
`
`1.1 BACKGROUND
`The proposed proprietary name,
`3166).
`
` is currently under review (OSE RCM #2011-
`
`1.2 PRODUCT INFORMATION
` is a dipeptidyl peptidase-4 (DDP-4) inhibitor and biguanide fixed combination
`product indicated as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus when treatment with both linagliptin and metformin is
`appropriate. The product will be available in three combination strengths of linagliptin and
`metformin hydrochloride (2.5 mg/500 mg, 2.5 mg/850 mg, and 2.5 mg/1000 mg). The
`recommended dose is one tablet by mouth twice a day with meals. Gradual dose escalation
`is recommended to reduce gastrointestinal side effects due to metformin. The maximum
`recommended dose is 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily. All
`dosing strengths will be available in 14 count sample bottles and retail bottles of 60, 180, and
`2000 tablets. The bottles should be stored at 25°C (77°F), with excursions permitted to 15-
`30°C (75°F -86°F) and protected from exposure to high humidity.
`
`METHODS AND MATERIALS REVIEWED
`2
`Using Failure Mode and Effects Analysis1 and our learning from postmarketing
`medication error data, the Division of Medication Error Prevention and Analysis
`(DMEPA) evaluated the following:
`• Container labels submitted August 17, 2011 (Appendix A)
`Insert labeling submitted August 3, 2011 (no image)
`•
`
`3 CONCLUSIONS AND RECOMMENDATIONS
`The container labels require revision prior to approval. See Section 3.1 (Comments to the
`Sponsor). We request these be communicated to the Sponsor prior to approval.
`DMEPA’s comments on the Insert labeling are included in Section 3.2 and will be
`discussed during the labeling meetings.
`If you have further questions or need clarifications, please contact Margarita Tossa, OSE
`Project Manager at 301-796-4053.
`
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`Reference ID: 3036918
`
`1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`3.1
`
`COMMENTS TO THE SPONSOR
`
`CONTAINER LABELS (ALL STRENGTHS; 14, 60, 180, AND 2000 COUNT BOTTLES)
`
`l. Revise the “Usual Dosage” statement to read: “Usual Dosage: See
`prescribing information.”
`
`CONTAINER LABELS (ALL STRENGTHS; 60, 180, AND 2000 COUNT BOTTLES)
`
`1.
`
`Increase the size and prominence of the middle portion of the NDC numbers
`(e.g. xxxx—XXXX—xx). Pharmacists use this portion of the NDC number to
`ensure the correct product is dispensed.
`
`CONTAINER LABELS (ALL STRENGTHS; 60 AND 180 COUNT BOTTLES)
`
`1. Delete the statement
`
` This statement could be confusing
`
`CONTAINER LABELS (ALL STRENGTHS; 2000 COUNT BOTTLES)
`
`1— _De1etethe statement—
`
`ALL CONTAINER LABELS FOR THE 2.5 MGI850 MG AND 2.5 MGl1000 MG
`
`STRENGTHS
`
`l. Revise the color blocking scheme used to highlight the stren
`the 2.5 mg/850 mg (i.e. royal blue) and the 2.5 mg/1000 mg
`labels to provide adequate differentiation between the two strengths. The
`current color blocking scheme are similar in color and matched to the bar
`graphics making it difficult to differentiate between the two strengths.
`
`statement on
`
`3.2
`
`COMMENTS FOR THE INSERT LABELING FOR DISCUSSION DURING THE LABELING
`MEETINGS
`
`FULL PRESCRIBING INFORMATION
`
`1. Dosage and Administration Section 2.1 includes a list of the available dosage
`tablet strengths. This information is pertinent and already included in the
`Dosage Forms and Strengths Section 3 of the PI and is therefore redundant.
`Revise to delete the statement that reads—
`
`Reference ID: 3036918
`
`

`

`2. Section 16 (How Supplied/Storage and Handling) includes statements which
`describe the physical appearance for each tablet strength. These statements are
`pertinent to and included in the Dosage Forms and Strengths Section of the PI;
`therefore, they are redundant and we recommend deleting them. Then, revise
`each of the statements which begin
` to read:
`
`“TRADE tablets (linagliptin and metformin HCl) 2.5 mg/500 mg are supplied
`as follows…;”
`“TRADE tablets (linagliptin and metformin HCl) 2.5 mg/850 mg are supplied
`as follows…;”
`and “TRADE tablets (linagliptin and metformin HCl) 2.5 mg/1000 mg are
`supplied as follows…”
`
`Reference ID: 3036918
`
`3
`
`7 pages of draft labeling has been withheld in
`full as B(4) CCI/TS immediately following
`this page
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`TERRI WOOD-CUMMINGS
`10/31/2011
`
`CARLOS M MENA-GRILLASCA
`10/31/2011
`
`CAROL A HOLQUIST
`10/31/2011
`
`Reference ID: 3036918
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`PATIENT LABELING REVIEW
`October 28, 2011
`
`Mary Parks, M.D., Director
`Division of Metabolism and Endocrinology Products
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Senior Patient Labeling Reviewer, Acting Team Leader
`Division of Risk Management
`Melissa Hulett MSBA, BSN, RN
`Patient Labeling Reviewer, Acting Team Leader
`Division of Risk Management
`
`Twanda Scales, RN, MSN/Ed.
`Patient Labeling Reviewer
`Division of Risk Management
`
`Subject:
`
`DRISK Review of Patient Labeling (Patient Package Insert)
`
`Drug Name (established
`name):
`Dosage Form:
`Application
`Type/Number:
`
`TRADE (linagliptin and metformin hydrochloride)
`
`Tablets
`
`NDA 201281
`
`Applicant
`
`Boehringer Ingelheim
`
`OSE RCM #:
`
`2011-354
`
`Reference ID: 3036137
`
`1
`
`

`

`1
`
`INTRODUCTION
`This review is written in response to a request by the Division of Metabolism and
`Endocrinology Products (DMEP) for the Division of Risk Management (DRISK) to
`review the Applicant’s proposed Patient Package Insert (PPI), for TRADE
`(linagliptin and metformin hydrochloride). The purpose of the Applicant’s
`submission is to provide an amendment to its 505(b)(2) New Drug Application
`(NDA 201281) and to revise proposed draft labeling. Additionally, the Applicant
`proposes updating the draft linagliptin and metformin prescribing information to be
`consistent with the approved Tradjenta (linagliptin) label.
`
`2 MATERIAL REVIEWED
`(cid:120) Draft TRADE (linagliptin and metformin hydrochloride) tablets, Patient Package
`Insert (PPI) received on August 3, 2011 and received by DRISK on October 20,
`2011.
`(cid:120) Draft TRADE (linagliptin and metformin hydrochloride) tablets, Prescribing
`Information (PI) received August 3, 2011 revised by the Review Division
`throughout the current review cycle and received by DRISK on October 20, 2011.
`(cid:120) Approved Trajenta (linagliptin), comparator labeling, dated May 2, 2011.
`(cid:120) Approved Glumetza (metformin hydrochloride extended-release), comparator
`labeling, dated April 13, 2011.
`
`3 REVIEW METHODS
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level. In our review of the PPI the target
`reading level is at or below an 8th grade level.
`
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelines for Prescription Labeling and Consumer Medication
`Information for People with Vision Loss. The ASCP and AFB recommended using
`fonts such as Verdana, Arial or APHont to make medical information more
`accessible for patients with vision loss. We have reformatted the PPI document
`using the Verdana font, size 11.
`In our review of the PPI we have:
`simplified wording and clarified concepts where possible
`(cid:120)
`ensured that the PPI is consistent with the prescribing information (PI)
`(cid:120)
`rearranged information due to conversion of the PI to PLR format
`(cid:120)
`removed unnecessary or redundant information
`(cid:120)
`
`Reference ID: 3036137
`
`2
`
`

`

`(cid:120)
`
`(cid:120)
`
`ensured that the PPI meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`ensured that the PPI is consistent with the approved comparator labeling where
`applicable
`
`4 CONCLUSIONS
`The PPI is acceptable with our recommended changes.
`
`5 RECOMMENDATIONS
`(cid:120) Please send these comments to the Applicant and copy DRISK on the
`correspondence.
`(cid:120) Our annotated versions of the PPI are appended to this memo. Consult DRISK
`regarding any additional revisions made to the PI to determine if corresponding
`revisions need to be made to the PPI.
` Please let us know if you have any questions.
`
`Reference ID: 3036137
`
`3
`
`13 pages of draft labeling has been withheld
`in full as B(4) CCI/TS immediately
`following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`TWANDA D SCALES
`10/28/2011
`
`LASHAWN M GRIFFITHS
`10/28/2011
`
`Reference ID: 3036137
`
`

`

`M E M O R A N D U M
`
`
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`___________________________________________________________________________________________
`
`
`
`CLINICAL INSPECTION SUMMARY
`
`September 15, 2011
`
`Mehreen Hai, Regulatory Project Manager
`Hyon (KC) Kwon, Clinical Reviewer
`Division of Metabolic and Endocrine Products (DMEP)
`
`Susan Leibenhaut, M.D.
`Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`
`Lauren Iacono-Connors, Ph.D.
`Acting Team Leader, Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`
`Jean Mulinde, M.D.
`Acting Branch Chief, Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`
`Evaluation of Clinical Inspections
`
`201281
`
`DATE:
`
`TO:
`
`
`
`
`
`
`
`FROM:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`THROUGH:
`
`
`
`
`
`
`
`THROUGH:
`
`
`
`
`
`
`
`SUBJECT:
`
`NDA:
`
`
`
`
`
`APPLICANT:
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`DRUG:
`
`linagliptin and metformin
`
`NME:
`
`
`
`No
`
`THERAPEUTIC CLASSIFICATION: Standard
`
`INDICATION: adjunct to diet and exercise to improve glycemic control in adults with
`
`type 2 diabetes mellitus
`
`CONSULTATION REQUEST DATE: April 5, 2011
`
`DIVISION ACTION GOAL DATE: November 18, 2011
`PDUFA DATE:
`
`
`November 19, 2011
`
`
`
`
`
`
`
`Reference ID: 3015790
`
`

`

`Page 2
`
`
`I. BACKGROUND:
`
`Clinical Inspection Summary
`
` NDA 201281 linagliptin and metformin
`
`Boehringer Ingelheim Pharmaceuticals, Inc. submitted NDA 201281 for the use of the
`combination of linagliptin and metformin as an adjunct to diet and exercise to improve
`glycemic control in adult