CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION.NUMBER:
`
`" 19-386/8018
`
`Trode Name:
`
`Brevib10c Injection '
`
`'
`
`Generic Name: Esmolol Hydrochloride
`
`Sponsor:
`
`Baxter Pharmaceutical Products Inc.
`
`I Approval Date: February 1-6, 2001
`
`Indications:
`'
`
`,
`
`7
`
`Short—Term control of heart rate inpatients
`with abnormally fast heart rhythms such as
`artrial fibrillation, atrial flutteror sinus
`tachycardia.
`A
`'
`'
`
`I
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH -
`
`APPLICA TION NUMBER}
`
`19-386/8018
`
`CONTENTS
`
`
`
`
`
`Apgoval Letter
`
`Approvable Letter
`
`Labeling
`
`
` :Reviews / Information Included in this NDA Review. j
`
`
`
`Medical Review(s)
`
`
`Chemistry Review(s)
`
`Pharmacology Review(s) '
`
`
`' Statistical Review(s)
`.
`
`Microbiology Review(s)
`
`Clinical PharmacolOgy/ Bio ‘ harmaceutics Review(s)
`
`
`
`
`aAdministrative/COrrespondence D0cnment(s)
`I
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`'
`
`APPLICATION NUMBER:
`19-386/5018
`
`APPROVAL LETTER ,
`
`'
`
`

`

`“g DEPARTMENTOFHEALTH&HUMANSERVICES
`
`‘
`
`
`
`PublicHealthService
`
`Food and Drug Admlnlstrafion
`Rockvllle MD 20857
`
`NDA. l9-386/S-018
`
`Baxter Pharmaceutical Products, Inc.
`Attention: Ms. Priya Jambhekar
`95 Spring Street
`New Providence, NJ 07974
`
`Dear Ms. Jambhekar:
`
`I Please refer to your supplemental new drug application dated August 30,2000, submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act for Brevibloc Premixed Injection (esmolol HClin
`sodium chloride)in 2500 mg/ZSOmL IntraVia Containers.
`
`We acknowledge receipt of yOur submissions dated January 12, and February 2 and 9, 200]. Your
`submission of January 12, 2001 constituted a complete response to our December 29, 2000 action
`letter.
`
`'
`
`This supplemental new erig application provides for a premixed injection packaged in 250 mL
`IntraVia containers (made of PL 2408 plastic bags With laminated foil over-pouch) containing two
`'
`pbrts. In addition, the word, “Injection” has been replaced with, “Concentrate” on the Ampul Label
`with Flag and the Ampuls Tray Label and the phrase, “Ready-to-Use” has been added to the Vial Label
`and Vials Tray Carton.
`
`We have completed the review of this supplemental application, as amended, and have concluded that
`; adequate information has been presented to demonstrate that the drug product'13 safe and effective for
`use as recommended'in the final printed labeling for the IntraVia Containers (package insert and
`immediate container labels) included'1n your January 12,2001 submission and the vial and ampul
`immediate container labels included1n your February 2, 2001 submission. Accordingly, the
`supplemental application is approVed effective on the date of this letter.
`
`When you make your production quantities of the labels, please change, “sodium acetate” to “sodium -
`acetate trihydrate” on the Ampuls Tray Label and, to be consistent, add the amounts of the inactive
`ingredients to the labels that do not have them already.
`
`We remind you of your postmarketing study commitments in your submissions dated January 12 and
`February 9, 2001. These commitments are listed below.
`
`

`

`NDA 19-386/S-018
`Page 2
`
`1. Baxter PPI makes a post-approval commitment to re-evaluate the subject formulation either to
`eliminate or significantly reduce overage of esmolol HCI added in the formulation and submit it as
`a supplement. The detailed plans ofaction for this commitment will be submitted by August 2001
`for the Brevibloc Premixed and Brevibloc Injection and February 2002 for the Brevibloc
`Concentrate. 'At the time you submit your plans, please include a date that the supplement(s) will
`be submitted.
`v
`
`,
`
`2. Baxter will tentatively reduce the specifications ofH in the drug product specifications
`
`from
`Baxter PPI will finalize these specifications after reviewing the 24 month
`stability data that will be available by August 2002.
`
`*
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under
`21 CFR 3 14.81(b)(2)(vii) and 314'.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include'expected'
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number ofpatients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`Y'Postmarketing Study Protocol", "Postmarketing Study Final Repel-t", or "Postmarketing
`Study Correspondence."
`
`In addition, please submit three copies ofthe introductory promotional materials that you propose to
`Use for this product, All proposed materials should besubmitted in draft or mock-up form, not final
`print. Please. submit one copy to this Division and two copies of both the promotional materials and
`the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD—42
`Food and Drug Administration
`5600 Fishers Lane
`.
`Rockville, Maryland 20857
`
`If a letter communicating important information about this drug product (i.e., a "Dear Health Care
`Professional" letter) is issued to physicians and others responsible for patient care, we request that you
`submit a copy of the letter to-this NDA and a Copy to the following address:
`.,
`
`_
`
`'MEDWATCH, HF-2
`FDA '
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`We remind you that you must comply with the requirements for an approved NDA Set forth under
`21 CFR 314.80 and 314.81.
`
`

`

`.' NDA 19-386/S-018
`
`Page 3
`
`If you have any questions, please call:
`
`Ms. Zelda McDonald 4
`
`Regulatory Health Project Manager
`(301) 5946333.
`
`Sincerely,
`
`.
`
`{See appended electronic signature page}
`
`Raymond J. Li'picky, MD.
`Director
`
`Division of Cardio—Renal Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`Raymond Lipicky
`2/16/01 08:35:08 AM
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH -
`
`APPLICA TI0N NUMBER:
`
`1 9—3 86/0 1 8
`
`APPROVABLE LETTER
`
`

`

` Food and Drug Administration
`
`Public Health Service
`
`Rockvlllo MD 20857
`
`NDA .1’9-386/8-01 3
`
`Baxter Pharmaceutical Products, Inc.
`
`Attention: Ms. Priya Jambhekar v
`95 Spring Street
`New Providence, NJ 07974
`
`Dear Ms. Jambhekar.
`
`Please refer to your supplemental new drug application dated August 30, 2000, submitted under section
`'505(b) of the Federal Food, Drug, and Cosmetic Act for Brevibloc (esmolol HCl1n sodium chloride)
`PremiXed Injection1n 2500 mg/ 250 mLIntraVia Containers.
`We acknowledge receipt ofyour submissions dated November 20 and 28, and December 5, 2000.
`
`'This supplement provides for a premixed injection packaged in 250 mL .InhaVi'a'containers (made ofPL 2408
`plastic bags With larninated foil-over-pouch) containing two ports Included with the submiSsion is revised
`draft labeling describing this change as well as recommendations by the Institute for Safe Medication
`Practices.
`-
`
`_
`
`y We have completed the review ofthis application, as amended, and it is approvablc. Before this application
`may be approved. however, it will be neecswry for you to submit final printed labeling (FPL) for the drug.
`' The labeling should be identical1n content to the enclosed marked—-up labeling (text for the package insert) and
`immediate container labeling includedin yourNovember 28, 2000 submission We also have the folloWing
`additional requests:
`1._ Please re-evaluate thenecessity for the high oveiage (10%) ofthe active ingredientin the drug product
`andprovide a commitment eitherto eliminate orsignificantly reduce itm a timelymanner. We currently do
`
`__not allowaverages unlessjustified bytaravoidable manufacturing losses. .
`
`
`.
`
`.
`
`I In addition, allprevious revisions as reflected1n the moSt recmtly approved labeling must be included. To
`facilitate review ofyour submission, please provide a highlighted or marked-up copy that shows the changes
`that are being made.
`'
`. Please submit 20paper capies ofthe final printed labeling ten ofwhich are individually mounted on heavy
`weight paper or similar matenal. Alternatively, you may subrr'rit the FPL electrbnically accordingto the
`guidance for industry titled Providing Regulatory Submissions in Electronic Format- NDAs (January
`1999).
`.
`_
`
`

`

`NDA 19-386/3-018
`
`Page 2
`
`Ifadditional information relating to the safety or effectiveness of this drug becomes available, revision of the
`labeling may be required.
`
`
`Brevibloc, Please note that the attached draft labeling
`,
`We believe that the
`for the-M——— We have made many changes to the
`enclosed marked-up draft that we think will avoid medication errors, while allowing the 10 mL Ampul (250
`~mg/ml) to remain on the market. We invite you, at your earliest convenience,%
`
`In addition, please submit three cepies ofthe introductory promotional materials that you propose to use for
`this product. All proposed materials should be submitted1n draft or mock-up. form, not final print. Please
`submit one copy to this Division and two copies ofboth the promotional materials and the packageinsert
`directly to:
`
`Division of Dmg Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`, 5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Within 10>days after the date ofthis letter, you are required to amend the supplemental application, notify us of
`your intent to file an amendment, or follow one ofyour other options under 21 CFR 314.110. In the absence
`of any such action FDA may proceed to withdraw the application. Any amendment should respond to all the
`deficiencies listed. We will not process a partial reply as a major amendment nor will the review clock be
`reactivated until all deficiencies have been addressed
`
`This product maybe considered to be misbranded under the Federal Food, Drug, and Cosmetic Act if1t[S
`marketed with these changes prior to approval ofthis supplemental application.
`.Ifyou have any questions, call:
`
`I
`
`Ms.Zelda McDonald
`
`Regulatory Health Project Manager
`(301), 594-5333.
`
`-
`
`Sincerely,
`
`g
`
`_
`Enclosure
`
`Raymond J. Lipicky, MD.
`Director
`Division ofCardio-Renal Drug Products
`Office ofDmg Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`Norman Stockbridge
`12/29/00 02:24:50 PM
`For RJ Lipicky
`
`

`

`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`
`FOOD AND DRUG ADMINISTRATION
`
`“elimin-
`
`9
`3°
`g
`
`*3
`“om"
`
`1
`'0,
`
`‘
`
`,
`- us Mail address:
`: FDA/CDERIHFD-11O
`5600 Fishers Lane
`Rockville, MD 20857
`
`'
`
`.
`
`Woodmont ll
`1451 Rockville Pike
`Rockviile. MD' 20852
`
`
`
`
`
`This document is intended only for the use of the party to whom it is addressed and may contain
`information that is privileged, confidential, and protected from disclosure under applicable law.
`If you are not the addressee, or a person authorized to deliver the document to the addressee. you are hereby notified
`that any review. disclosure, dissemination copying. or other action based on the contentof this communication is not
`
`authorized.
`If you have received this document'In error please immediately notify us by telephone and return it to:
`
`CDER, DCRDP HFD—110; 5600 Fishers Lane; Rockville. MD 20857
`
`
`
`Transmitted to FAX Numbel:
`
`908-286-7269
`
`Attention:
`
`Ms. Priya Jambhekar
`
`Company Name:
`
`Baxter
`
`Phone:
`
`908-286—7215
`
`Subject:
`
`Approvable Letter I
`
`Date:
`
`_ Pages including this sheet:
`
`From:
`Phone:
`Fax:
`
`I
`
`,
`
`12/29/00
`
`25
`
`Zelda'McDonald
`301-594-5333
`301-594-5494
`
`PLEASE LET ME KNOW YOU RECEIVED THIS. THANKS!
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH '
`'
`
`APPLICA TION NUMBER:
`
`19-386/8018
`
`CHEMISTRY REVIEWflS)
`
`

`

`NDA 19—386/01 8 amendments
`
`
`
`CHEMIST'S REVIEW
`
`'
`
`3.
`
`
`
`
`
`5. Drug Name
`Brevibloc
`
`10. How Dispensed
`ER): DOTC
`
`
`
`nscewgmq
`
`0
`
`on
`
`
`
`1. ORGANIZATION
`2. NBA Number
`‘
`HFD-l 10
`19—386
`
`
`,
`
`Name and Address of Applicant (City & State)
`_4. Supplement(s)
`Baxter Pharmaceutical Products Inc.
`'
`Number(s)
`Date(s)
`
`
`
`95 Spring Street
`SCP/018
`08/30/00
`New Providence NJ 07974
`
` Amendments & Other (reports,
`6. Nonproprietary Name
`' Esmolol HCl
`etc) Dates
`Amendments - Dated
`
`8. Supplement Provides For:
`01/12/01
`
`
`
`02/02/01
`Packaging of the currently approved 10 mg/mL Brevibloc
`
`
`02/09/01
`premixed Injection (Esmolol hydrochloride in sodium chloride) in
`
`
`an additional configuration, 250 mL in IntraVia Containers (made
`
`
`of PL 2408 plastics bags with laminated foil overpouch) containing
`
`
`
`
`
`
`.9. Pharmacological Category
`11. Related IND(s)/
`Anti—adreneric
`i rece-tor
`.
`NDA(s)/DMF(s)
`
`
`
`
`
` 13..
`12. Dosage Form(s)
`Potency(ies)
`Intravenous injection
`250mg/mL lOmL amp
`
`10 m_ mL IOmL vial
`
`14. Chemical Name and Structure
`
`
`
`15. Records/Reports
`Current
`.
`methyl p-[2-hydroxy—(isopropylamino)propoxy]
`
`
`hydrocinnamate hydrochloride
`EYes DNo
`
`
`
`
`Reviewed
`
`
`HCl
`E Yes D No
`
`
`
`
`This review is of a prior approval supplement for a premixed injection packaged in 250 mL lntraVia
`containers. These amendments are in response to our approvable letter of December 29, 2000.
`Firm is committing that they will evaluate the overage issue and also will evaluate tentatively proposed
`specifications of—- for the degradation product 45‘—
`On our request, firm has further clarified the phase 4 commitments and has included a specific time lines to
`completion as under:
`-
`.
`'
`Commitment 1: Firm will providedetailed plan of action within 6 months by 08/2001 for re-evaluation of the
`formulations for B'revibloc Premixed in 250 mL bags and Injection in 10 mL vials. And plan of action for the r
`
`concentrate in ampuls will follow within 'six months by 02/2002.
`,
`,
`‘
`.
`1
`
`
`Commitment 2: .Firm'will review the. 24-month stability data on the .L—o'fBrevibloc Bag by August 2002 '
`‘
`
`to confirm the proposed specification ofj—for the degradation product, .,
`
`' Labeling: Firm states that the previous package insert has listed one of the in actives sodium acetate
`
`trihydrate as sodium acetate by mistake. The proposed revised package insert now has this ingredient
`
`correctly mentioned as sodium acetate trihydrate. There is no change in formulation but correct
`representation of the inactive ingredient.
`‘
`
`Cartons labeling: It’s noticed that In one of the cartons labeling submitted in amendment of 1/12/01,
`has inactive ingredient sodium-acetate mentioned instead of corrected representation as sodium
`acetate trihydrate. Also in some cartons labels there is mention of the amounts of inactive ingredients
`and some carton labels no amounts of in active ingredients are described. Firm must correct these
`discrepancies in package/cartons labels in FPL.
`
`
`16. Comments:
`
`
`
`
`
`
`_
`
`
`
`
`
`
`
`
`
`
`
`
`_
`
`
`
`
`1'7. Conclusions and Recommendations
`A roval letter ma be issued.
`
`_
`
`‘
`
`.
`
`I
`
`'
`REVIEWER
`18.
`
`'_ Name
`JV Advani
`
`
`
`-
`
`Signature
`-
`
`.
`
`'
`
`*
`
`I
`
`V
`
`.
`
`Date Completed
`‘Febmary 13, 2001
`
`
`
`
`1
`
`
`
`.
`
`
`
`
`
`
`
`
`
`

`

`NDA 19—386/018 amendments
`
` Distribution:
`
`Original Jacket
`
`

`

`J. V. Advani
`2/13/01 02:32:38 PM
`CHEMIST
`
`Kasturi Srinivasachar
`2/13/01 03:15:52 PM
`CHEMIST
`
`

`

`NDA 19-386/018
`
`_
`
`CHEMIST'S REVIEW
`_
`
`
`
`1. ORGANIZATION
`HFD~110 '
`
`2. NBA Number
`19—386
`
`3. Name and Address of Applicant (City & State)
`Baxter Pharmaceutical Products Inc.
`95 Spring Street
`New Providence NJ 07974
`
`
`
`
`4. Supplement(s)
`Number(s)
`SCP/O 18
`
`Date(s)
`08/30/00
`
`
`
`1
`
`»
`
`
`
`'
`
`5. Drug Name
`' Brevibloc
`
`6. Nonproprietary Name
`Esmolol HCI
`
`7. Amendments & Other (reports,
`etc) Dates
`
`
`
`
`
`
`
`
`
`
`
`
`8. Supplement Provides For:
`- Packaging of the currently approved 10 mg/mL Brevibloc
`premixed Injection (Esmolol hydrochloride in sodium-chloride) in
`an additional configuration, 250 mL in IntraVia Containers (made
`of PL 2408 plastics bags with laminated foil overpouch) containing
`two I HTS.
`
`
`
`9. Pharmacological Category
`-
`
`i rece-tor
`Anti—adrener_ic
`
`10. How Dispensed
`ERx DOTC
`
`
`12. Dosage Form(s)
`
`Intravenous injection
`
`
`
`
`
`14. Chemical Name and Structure
`methyl p-[2—hydroxy—(isopropylamino)propoxy]
`hydrocinnamate hydrochloride
`
`
`Amendment of 1 1/20/00
`
`Amendment of 1‘1/28/00
`Amendment of 12/05/00*
`
`
`(*withdrawal of Aibonito PR site)
`
`
`
`i
`
`. HsC’°‘n’¥©-°/\K‘§
`
`"
`
`o
`
`11. Related IND(s)/
`NDA(s)/DMF(s)
`DMF 11691
`
`
`
` l3.
`Potency(ies)
`
`25‘0mg/mL lOmL amp
`
`
`10 m_ mL IOmL vial
`
`15. Records/Reports
`Current
`
`
`
`
`EYes DNO
`
`
`
`
`Reviewed
`
`
`HCl
`[:1 No
`8 Yes
`
`
`
`
`
`_
`
`OH
`
`
`Firm has provided the 6 months stability data in the ready to use formulation in the 250 mL IntraVia
`
`
`containers. Firm ha also provided the manufacturing formula and executed batch records for new
`configuration, 10 mg/mL, 250 mL non-PVC bag. Firm has provided the revised labeling with relevant
`changes
`Cont’d
`
`
`17. Conclusions and Recommendations
`_
`_
`
`This P.A. supplement may be approved from the stand point ofchemistiy and draft labeling. Refer
`
`microbiology and draft labeling reviews filed with this supplement. All establishments sites are‘acceptable.
`
`(Firm has withdrawn plastic container assembly site in Aibonito, PR, amendment of 12/05/00)
`.
`Copy of acceptable BER is attached. FollOWing recommendation were made in teleconference with the firm
`
`on 11/27/00.
`-
`
`16. Comments:
`
`
`
`
`
`
`
`1) Storage statement of the inner plastic-bag and outer foil pouch should be changed to read “Store at 25°C
`
`(77°F);excursion permitted to 15-30°C (59°-86°F). See USP Controlled Room Temperature .
`2) The high overage ——+ and acceptance criteria;—- for
`'are notjustified based on the
`stability
`data presented. _
`'
`'
`Firm has now revised the bag labels and included the storage statement as requested (amendment 11128/00).
`
`However the firm has to revise also the storage statement in the package'insert.
`Firm is committing that they will evaluate the overage issue and specifications.
`
`18.
`
`REVIEWER
`
`Name
`IV Advani
`
`I
`
`7
`
`Signature
`
`'
`
`-
`
`I
`
`Date Completed
`Nov. 28 2000
`
`'
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Distribution:
`Original Jacket [21 Reviewer
`Division File
`cso '
`
`
`

`

`
`
`A 1§ 552(b)(4) Trade Secret / Cnfldentlal
`
`-_ § ‘ 552(b)(5); Deliberative IPrO-eess l'_
`
`__ i§.552:b)(43)Draft Laelm .-
`
`-
`
`"
`
`

`

`‘
`J. V. Advani
`12/20/00 04:24:25 PM
`CHEMIST
`
`Kasturi Srinivasachar
`12/20/00 05:22:07 PM
`CHEMIST
`
`

`

`. CENTER FOR DRUG EVALUATION AND
`‘
`. RESEARCH
`.
`
`APPLICA TION NUMBER:
`
`19-386/8018 '
`
`V MICROBIOLOGY REVIEW
`
`

`

`REVIEW TO HFD-llO
`
`OFFICE OF NEW DRUG CHEMISTRY
`MICROBIOLOGY STAFF/HFD-805
`MICROBIOLOGY REVIEW #1 OF NBA
`
`15 December 2000
`
`NDA: l9-386/SCP-018
`
`TYPE OF SUPPLEMENT: Prior Approval
`
`SUPPLEMENT PROVIDES FOR: A ready to use concentration ofthe
`drug product in a new container (LVP).
`
`l.
`
`2.
`
`3.
`
`4.
`'
`
`'
`
`APPLICANT/SPONSOR:
`~
`
`'
`
`Baxter Pharmaceutical Products, Inc.
`95 Spring Street
`New Providence, New Jersey 07974-
`
`5 .
`
`6.
`
`MANUFACTURING SI'IE: Baxter Healthcare Corporation
`'
`Highway 221 North
`Marion, North Carolina 28752 ,
`
`DRUG PRODUCT NAME:
`PrOprietary: Brevibloc®
`Nonproprietary: Esmolol hydrochloride
`Drug Priority Classification:
`
`. 7.
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY: 250mL plastic bag for IV, 10 mg.mL
`
`
`
`8.
`
`9.
`
`1.
`2.
`3.
`4.
`
`5.
`6.
`
`METHOD(S) OF STERILIZATION:
`
`, PHARMACOLOGICAL CATEGORY:
`
`DOCUMENT/LETTER DATE:
`RECEIPT DATE:
`CONSULT DATE:
`DATE OF AMENDMENT:
`
`August 30, 2000
`August 31, 2000
`September 5, 2000
`na
`'
`
`October 23, 2000
`ASSIGNED FOR REVIEW:
`SUPPORTING/RELATED DOCUMENTS: DMF 11,691
`
`REMARKS: The validation information for the ———-———— is
`located in Baxter DMF 11,691.
`
`

`

`> Microbiologist’s Review #1
`NDA l9-386/SCP-018 (Breviblocm)
`
`
`D.
`
`' CONCLUSIONS: This submission is recommended for approval on the basis of
`'product quality microbiology.
`'
`
`'
`
`Bryan S. Riley, Ph.D.
`Microbiology Reviewer
`
`cc.:
`
`Original NDA 19—3 86
`HFD llO/Division File
`HFD 110/2. McDonald
`‘ HFD 110/1. Advani
`HFD 805/Consult File
`
`HFD 805/‘B. Riley
`
`. Drafied by: Bryan Riley, Ph.D.
`RID initialed by: Peter Cooney, Ph.D.
`
`filename: C:\data\data\word\nda\s\l93 8651 8
`
`Page 2 of4
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`j
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`'-
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`

`

`Bryan Riley
`12/22/00 12:25:36'PM
`MICROBIOLOGIST
`
`Peter Cooney
`12/22/00 01:41:59 PM
`MICROBIOLOGIST
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`'
`
`RESEARCH I
`
`. APPLICATIONNUMBER:
`
`19-3 86/S018
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`DOCUMENTS
`
`'
`
`-
`
`

`

`RHPM Review of Final Printed Labeling
`NDA 19—386/8-01 8
`
`Date of Submission:
`Date Received:
`Date of Review:
`Applicant Name:
`Product Name:
`
`>
`
`January 12, 2001
`January 26, 2001
`January 26, 2001
`Baxter Pharmaceutical Products Inc.
`Brevibloc Premixed Injection (esmolol .HCl in sodium chloride), in
`2500 mg/250 mL lntraVia Containers
`
`,
`>
`,
`Evaluation:
`This submission provides for final printed labeling revised to include a description of the new pre-mixed
`bag, Dosing and AdministratiOn instructions and How Supplied information for the pre-mixed bag. The
`changes are too extensive to list here. Except for a few minor editorial changes, the labeling is identical
`to the marked-up dratt labeling that accompanied the December 29, 2000 approvable letter and the
`agreements made in the January 5, 2001 teleconference. The agreements per the teleconference are as
`follows: ‘
`
`.
`
`. It was agreed that the three dosage forms can be separated at the beginning of the labeling as Baxter had
`originally proposed, and the foot note regarding the tradenames can remain at the end of the labeling.
`Baxter will substitute “Concentrate” for “Injection” when describing the ampul, however, use of“Bolus”
`_ instead of “Injection” when describing the vial will be addressed in a future submission. The word
`“container” will be replaced by “bag” throughout the labeling. Although not mentioned in the minutes,
`we agreed with Baxter’s proposal to include a patient information label that can be applied to theInner
`bag. Therefore, the sentence, “Fill out the patient information label supplied and apply to the'Inner bag”
`has been added to the DOSAGE AND ADMINISTRATION section.
`
`There are no other changes from the last approved package insert.
`
`The word, “Injection” has been replaced With, “Concentrate” on the Ampul Label with Flag and the
`Ampuls Tray Label.‘
`
`The phrase, “Ready-to—Use” has been added to the Vial Label and Vials Tray Carton.
`
`When Baxter makes the production quantities of the labels, they should change, “sodium acetate” to
`“sodium acetate trihydrate” on the Ampuls Tray Label and, to be consistent, add the amounts of the
`inactive ingredients to the labels thatdo not already have them. This will be requestedin the approval
`letter.
`
`Recommendation:
`An approVal letter should'issue for this supplement as set forth under 21 CFR 3 14.70 (b) (3X1) [Any
`. changein labeling].
`
`‘
`cc: orig. NDA
`I-[FD-l 10
`HFD-l 10/McD0nald
`HFD_-1 10/Blount
`I-IF-2
`-
`
`.Zelda'McDonald, RHPM
`
`

`

`Zelda McDonald
`- 2/20/01 03:46:20 PM
`CSO
`
`'
`
`

`

`DIVISION OF CARDIO-RENAL DRUG PnonUCrs
`FOOD AND DRUG ADMINISTRATION -
`
`ofl‘m‘“ ,
`.
`E.“ / USMailaddress:
`3 C FDA/CDER/HFD—l 10
`
`5600 Fishers Lane
`Rockville, MD 20857
`
`2
`he
`
`,
`
`Woodmont II
`1451 RockvillePike
`.Rockville, MD 20852
`
`
`
`This document is intended only for the use 'of the party to whom it is addressed and may
`contain information that is privileged, confidential, and protected from disclosure under
`applicable law.
`.If you are not the addressee, or a person authorized to deliver the document to
`
`
`the addressee, you are hereby notified that any review, disclosure, disSeminatiOn, copying, or
`
`
`other action based on the content of this communication is not authorized; If you have received
`this document in error, please immediately notify us by telephone and return it to:
`CDER,
`
`
`DCRDP
`I D—l 10 ; 5600 Fishers Lane; Rockville, MD' 20857
`
`
`
`
`Transmitted to FAX Number:
`
`908-286—7269
`
`' Attention:
`
`Ms. Priya Jambhekar
`
`Company Name:
`Phone:
`
`_ Baxter
`I
`908-286-7215
`
`Subject:
`
`Minutes of 1/5/01' Telecon
`
`Date:
`
`' 1/23/01
`
`Pages including this sheet:
`
`4 '
`
`i From:
`Phone;
`Fax:
`
`Zelda McDonald
`301-594-5333
`-
`301-594-5494
`
`YOU ARE RESPONSIBLE FOR NOTIFYING US OF ANY SIGNIFICANT .
`DIFFERENCES IN UNDERSTANDING YOU MAY HAVE REGARDING THE
`MEETING OUTCOMES (AS REFLECTED IN THE MINUTES).
`-
`
`I PLEASE LET ME KNOW ‘YOU RECEIVED THIS. THANKS!
`
`cc:
`
`, Orig.
`HFD-l 10
`
`HFD-l lOMcDonald/Matthews
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`Division or Cardio-Renal Drug Products
`
`.
`
`Public Health Service
`. Memorandum
`‘
`
`Date
`From
`Subject
`To
`
`: December 27, 2000
`: Director. Division of Cardio-Renal Drug Products HFD-110
`: Approvability of NBA 19-386 Esmoiol Premix (250 ml/10mg per ml), Baxter Healthcare
`:NDA File
`
`_,
`
`Baxter has formulated a 250 ml premix of esmolol (l 0mglml) in a sterile, isotonic solution contained in a
`bag meant to be used for infusion of esmolol without the need for dilution. Previously, there was a
`10 ml
`Ampul (containing a total of 2,500 mg esmolol, 250 mg/ml) that required on-s-ite dilution to prepare a
`similar solution for infusion, except that the on-site health care professionals might not have used an
`isotonic solution for dilution.
`
`There is a It) ml vial (containing a total of 100 mg esmolol, 10 tug/ml) that was used for giving “loading
`doses", one minute infusions. The current premix container has a port that can be used for getting the
`“loading doses" directly from the same container that is being used for longer duration infusions.
`
`From a manufacturing and controls vantage point, everything is in order (except as noted in the
`“approvable” letter. Everything is order except for labeling.
`
`’
`
`OPDRA has provided an insightful review and points out that the use of esmolol has been associated with
`an incidence of medication errors that were associated with the use of the concentrated solution (250
`mglml) solution for infusion without appropriate dilution. Indeed, these errors did Occur but with
`
`apparently decreasing frequency.
`.w The premix bag for
`infusion eliminates the need for on-site formulation of IO mg/ml infusion formulation.
`
`The need for an available formulation ofesmolol that contains greater than a 10 ngml concentration
`of esmolol.
`.
`There are certainly times in critical care medicine when the total volume of solution infusedintravenously
`is critical. Although all loading and chronic infusion dosingIs outlined'In the form ofusIng a lO/mg/ml
`concentration, dosing is specified in terms of micrograms or milligrams/kg/Ininute. VFor heavier patients,
`when dosing is specified'in terms of ml/minute, this can amount to as much as 132 ml/bour. Guessing that
`-._‘ in a patient with renal shutdown and recent onset atIiaI fibrillation that at least a 6 hour treatment with
`esmolol might be needed, the esmolol treatment alone (using 10 mglml concentrations) would exceed the
`
`- fluid limits that are allowed over an entire 24 hour day.
`
`
`
`‘iiifi
`
`
`
`
`So labelingIs important here LabelingIs a guessing game ItIs a guessas what language
`communicates what, and what language prevents errors. Over the years, I think the data indicate that the
`' FDA’s guesses (along with Baxter) have improved language and that errors have decreased (5 reports'In
`interval 1997-1999, compared to 10'In the interval [992- 1.994) The premix formulation should make that
`even better. ———'—-————————————_A
`
`
`_
`
`LabelingChanges That Are Needed
`
`Page 1 of draft package insert
`The order (that is the_appearance from the top of the page) of formulations should be:
`"__________
`
`

`

`-
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`L
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`5
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`Page(s)_Wit'eld
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`__ § 552(b)(4) Trade S'ecret/Chnfiehtial
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`'
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`I
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`L§ .552‘(H)1(45)raft Labeling
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`1
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`

`

`Norman St'ockbridge
`12/29/00 02:13:07 PM
`MEDICAL OFFICER
`
`For RJ L'ipicky
`
`sm-
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`Division ‘or Cardio—Renal Drug Products _
`
`‘
`
`v
`.
`Public Health Service
`Memorandum
`
`Date
`From
`Subject
`
`To
`
`_
`: December 28, 2000
`-
`‘
`: Director. Division of Cardio—Renal Drug Products, HFD-110
`: Approvabiiity of NDA 19-386. Esmolol Premix (250 mi/10mg per ml). Baxter Healthcare .
`Addendum to Approvability Memo of 12/27/00
`’
`.
`: NDA File '
`
`. Upon looking at the’revised drah labeling, based on my I2/27/00 memorandum, it appears to me that there
`is an even better way to avoid the problems of medication errors that occur simply because of similar
`names.Indeed there are only two formulations of esmolol:
`-
`10 mg/rnl, which comes in total volumes of 10 ml or 250 ml
`and
`.250 mg/ml, which comes in a total volume of [,0 ml.
`-
`»
`Part of the problem is’ that both l_0 ml volumes are called Brevibloc T”.
`'
`.
`Indeed ifboth the IQ and 250 ml volumes of 10 mg/ml were called Brevibloc TM Premix (as they are now
`classified1n the Division marked-up draft labeling) and the 250 mglml ampul was called Brevibloc 1“
`Concentrate, a semantic and confusingIssue might be resolved. I think this should be suggested to Baxter
`in the approval: le letter.
`
`Baxter can, as they evaluate inventory, and manufacturing schedules, submit another supplement‘that
`changes nothing other than container labeling and the name in the package insert.
`
`For now, the current supplement is approvable according to the marked up version of the package insert.
`
`The immovable letter should sav:
`\
`
`-———-———‘——-———-—' .-We have made many changes to
`the enclosed marked-up draft that we thinkwill avoid medication errors, while allowing the IO mL Amnul
`
`(250 rug/ml) to remain on the market.
`
`
`There are also a few corrections that need to be made to the 12/27/00 draft package insert.
`'
`Page 1 Brevibloc Injection, the last sentence under that heading should read;
`’
`_
`SEE DOSAGE AND ADMINISTRATION: Directions for use of the 10 mL Ampul (250
`
`mg/mL).The directions for use ofthe 10 mL Ampul (250 mg/mL) is new, but1s‘ the appropriate reference
`
`for where to look
`_
`_ p
`'
`‘
`_
`Page 2 Bottom ofthe page, in the section for Brevibloc 1nject10n, alter the 2500mg,10 mL Ampul — where
`it describes the esmolol concentration- should read:
`,
`'
`Each mL 250 mg_Esmolol Hydrochloride instead of esmololHCL,
`_ After the sentence that ends with.“ “hydrochloric acid added, as necessary, to adjust pH to 3.55.5",there
`should be a repeat warning and instructions for where to look.
`'
`NOT FOR DIRECT INTRAVENOUS USE. AMPUL MUST BE DILUTED PRIOR TO ITS
`INFUSION. SEE DOSAGE AND ADMINISTRATION: Directions for use of the 10 mL Ampul (250
`mg/mL).
`
`‘
`
`
`Page 10 Last paragraph, I" sentence that reads Maintenance infusion maybe continued for as long as—
`There should be a sentence before it and the existing sentence should be modified so thefirst two
`sentences of the paragraph would read:
`'
`
`

`

`In the abse‘ncerof loading doses, constant infusion of a single concentration of esmolol reaches
`pharmacokinetic and pharmaco'dynamicsteady-state in about 30 minutes. Maintenance infiisions (with or
`without loading doses) may be continued for as long as 24 hours;
`-
`
`\______‘___~—_
`
`
`Elapsed
`Time
`
`(Minutes)
`
`Page 14 Directions for Use of the Premixed Bag. First paragraph, all of the BREVIBLOC PREMLXED TM
`need to be changed to BREVIBLOC TM PREMIXED.
`>
`
`Then it is ready to go. Dr. Stockbridge will sign this and the previous memorandum as well the approvable
`letter.
`'
`'
`
`

`

`Norman Stockbridge
`12/29/00 02:15503 PM
`MEDICAL OFFICER
`For RJ Lipicky
`
`

`

`Teleconference Minutes
`
`7
`
`Telecon Date:
`Date Requested:
`NBA:
`IND:
`
`.
`
`January 5, 2001
`Our request: January 3, 2001
`l9-386/S-018
`20,015
`
`Spenser:
`Type:
`Classification:
`
`Baxter
`Guidance
`C
`
`Telecon Chair:
`- Telecon Recorder:
`
`-
`
`Raymond Lipicky, MD.
`Zelda McDonald
`
`External Participant Lead:
`
`Priya Jambhekar
`
`F___‘DA.
`Raymond Lipicky, M.D.
`Zelda McDonald
`
`'
`
`7
`Baxter:
`Priya J ambhekar
`-Marc Hoffman, MD.
`Raul Tr-illo,'M.D.
`Kent Allenby Sr., M.D.
`Carl Strotz
`'
`
`_
`
`.
`
`.
`
`'
`
`-
`
`\
`
`_
`_
`Director, Div. of Cardio-Renal Drug Products, HFD] 10
`RHPM, HFD-l 10
`'
`.
`
`-
`-
`Director,'Regulatory Affairs
`Director, Drug Safety and Clinical Research
`Senior Director, Marketing
`Vice President, Clinical Research and-Medical Affairs
`Manager, Labeling
`
`Background:
`Baxter submitted a chemistry supplement with labeling on August 30, 2000 that provided for a
`pre-mixed injectionpackagedIn 250 mL IntraVia Containers. Approvable letter with marked-up
`labeling for this supplement issued on December 29,2000. The main thrust ofth1s supplement
`was to avoid medication errorsthat can/have occur(red) with the ampul that requires dilution
`.before use.
`
`,
`
`
`
`In addition, Baxter submitted proposals for a
`revised statistical plan fer their proposed Brevibloc pediatric study (20,015-004) on
`December 22 and 27,2000 respectiver The Division requested this telecon to discuss the
`_ supplementand Baxter’s two proposals.
`,
`‘
`Telecon:
`l. The Agency grouped the 10 mi. vials and 250 mL IntraVia containers as a pre-rnixeddosage .
`form and separated that ampuls farm this p