CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`19-386/5-021
`
`Administrative Documents
`
`

`

`RHPM Review of Drafl Labeling
`NDA19-386/S-021
`
`Date of Submissions:
`Date of Review:
`Applicant Name:
`Product Names:
`
`'
`
`October‘24, 2002
`December 3, 2002
`Baxter Healthcare Corporation, Anesthesia & Critical Care
`Brevibloc Injection 10 mg/mL in 10 mL ready-to-use vials (19-3 86/S-021)
`
`Evaluation:
`
`This submission represents the completion of a phase 4 commitment which was agreed upon by Baxter Healthcare
`Corporation, Anesthesia & Critical Care with the approval of a supplemental application, 8-018, for Brevibloc
`Premixed Injection 10mg/mL packaged in 250 mL bags on February 16, 2001. This commitment is as follows:
`
`Baxter PPI makes a post-approval commitment to reevaluate the subject formulation to either eliminate or
`significantly reduce overage of esmolol HCl added in the formulation, and submit it as a supplement. The
`detailed plans of action will be submitted by August 2001 for the Brevibloc Premixed Injection and by
`February 2002 for the Brevibloc Concentrate. At the time you submit your plans, please include a date the
`at the supplement(s) will be submitted.
`
`Baxter Healthcare Corporation, Anesthesia & Critical Care proposes the following labeling changes to the package
`insert:
`
`1. The addition of the following to the title of the package insert:
`
`BREVIBLOC PREMIXED INJECTION
`
`(Esmolol Hydrochloride)
`DOUBLE STRENGTH
`
`Ready-to—use Bags
`100 mL Bags
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride
`For Intravenous Use
`Can be used for direct intravenous use.
`
`Esmolol Hydrochloride concentration = 20 milligrams/mL (20,000 micrograms/mL)
`Single Patient Use Only
`No Preservatives Added
`
`2. The addition of the following line to the title under the BREVIBLOC INJECTION, Ready-to-use Vials, lOmL
`Vials:
`.
`
`ISO-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride
`
`3. The addition ofthe following paragraph at the end of the DESCRIPTION section, Brevibloc Premixed
`Injection subsection:
`
`.2000 mg, 100 mL Single Use Premixed Bag DOUBLE STRENGTH —- Each mL contains 20 mg Esmolol
`Hydrochloride, 4.1 mg Sodium Chloride, USP and Water for Injection, USP; buffered with 2.8 mg Sodium
`Acetate Trihydrate. USP and 0.546 mg Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric
`Acid added,as necessary, to adjust pH to 5.0 (4.5-5.5). The calculated osmolarity is 312mOsmoI/L. The
`100 mL bag is non-latex, non-PVC IntraVia bag with dual PVC ports. The IntraVia bag is manufactured
`from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach
`out certain chemical compounds from the plastic in very small amounts; however, biological testing was
`supportive of the safety of the plastic container materials. See DOSAGE AND ADMINISTRATION,
`Directions for Use of the Premixed Bag for additional information.
`
`4. The DESCRIPTION section, Brevibloc Injection subsection has been changed from:
`
`

`

`BREVIBLOC INJECTION is a clear, colorless to light yellow, sterile, nonpyrogenic solution.
`100 mg, 10 mL Single Dose Vial — Each mL contains 10 mg Esmolol Hydrochloride and Water
`for Injection, USP; buffered with 2.8 mg Sodium Acetate Trihydrate, USP and 0.546 mg Glacial Acetic
`Acid,'USP. Sodium Hydroxide and/or Hydrochloric Acid added, as necessary to adjust pH to 4.5-5.5.
`
`To:
`
`BREVIBLOC INJECTION is a clear, colorless to light yellow, sterile, nonpyrogenic, iso—osmotic solution
`of esmolol hydrochloride in sodium chloride.
`100 mg, 10 mL Single Dose Vial -— Each mL contains 10 mg Esmolol Hydrochloride, 5.9 mg
`Sodium Chloride, USP and Water for Injection, USP; buffered with 2.8 mg Sodium Acetate Trihydrate,
`USP and 0.546 mg Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid added, as
`necessary to adjust pH to 5.0 (4.5-5.5).
`
`5.
`
`In the DOSAGE AND ADMINISTRATION section, the subsection heading has been changed from:
`
`Directions for Use of Brevibloc Premixed Injection
`
`To:
`
`Directions for Use of Brevibloc Premixed Injection and Brevibloc Premixed Injection DOUBLE
`STRENGTH
`
`6.
`
`In the DOSAGE AND ADMINISTRATION section, Directions for Use of Brevibloc Premixed Injection
`and Brevibloc Premixed Injection DOUBLE STRENGTH subsection, the paragraph has been changed from:
`
`This dosage form is prediluted to 250 mL to' provide a ready-to-use, iso-osmotic solution of 10 mg/mL
`esmolol hydrochloride in sodium chloride. Do not introduce additives to BREVIBLOC PREMIXED
`INJECTION. See Directions for Use of the Premixed Bag for additional information.
`
`To:
`
`This dosage form is prediluted to 100 or 250 mL to provide a ready-to—use, iso-osmotic solution of 20 or 10
`mg/mL esmolol hydrochloride in sodium chloride. Do not introduce additives to BREVIBLOC
`PREMIXED INJECTION or BREVIBLOC PREMIXED INJECTION DOUBLE STRENGTH. See
`
`Directions for Use of the Premixed Bag for additional information.
`
`7.
`
`In the DOSAGE AND ADMINISTRATION section, Directions for Use of the Premixed Bag subsection,
`the first sentence has been changed from:
`
`BREVIBLOC PREMIXED INJECTION is provided in 250 mL IntraVia bags, which are ready-to-use, non-
`latex, non-PVC bags with two ports, a medication port and a delivery port.
`
`To:
`
`I BREVIBLOC PREMIXED INJECTION and BREVIBLOC PREMIXED INJECTION — DOUBLE
`STRENGTH are provided in 250 mL and 100 mL IntraVia bags, which are ready-to-use, non-latex, non-
`PVC bags with two ports, a medication port and a delivery port.
`
`8. The following paragraph was added to the end of the DOSAGE AND ADMINISTRATION section,
`Directions for Use of the Premixed Bag subsection:
`
`The Brevibloc Premixed Injection DOUBLE STRENGTH contains Esmolol Hydrochloride at a
`concentration of 20 milligrams/mL. When using 20 milligrams/mL concentration, a loading dose of 0.5
`milligrams/kg infused over 1 minute period of time, for a 70 kg patient, is 1.75 mL. The loading dose can
`be removed from the medication port of the premixed bag.
`
`

`

`9.
`
`In Figure 1. Two-Port IntraVia Bag, the text to describe the two ports, “Medication Port (for withdrawing initial
`bolus)” and “Delivery Port”, Was deleted.
`
`10. In the DOSAGE AND ADMINISTRATION section, Directions for Use of the Premixed Bag subsection, the
`last sentence under the directions TO OPEN has been changed from:
`
`Do not introduce additives to BREVIBLOC PREMIXED INJECTION.
`
`To:
`
`Do not introduce additives to BREVIBLOC PREMIXED INJECTION or BREVIBLOC PREMIXED
`INJECTION — DOUBLE STRENGTH.
`
`11. The first sentence in the DOSAGE AND ADMINISTRATION section, Directions for Use of the 10 mL
`Ready-to-use Vial (10 milligrams/mL) has been changed from:
`
`This dosage form is prediluted to provide a ready to use lOmg/mL concentration recommended for
`BREVIBLOC intravenous administration.
`
`To:
`
`This dosage form is prediluted to provide a ready-to-use, iso-osmotic solution of 10mg/mL esmolol
`hydrochloride in sodium chloride recommended for BREVIBLOC intravenous administration.
`
`12. The following has been added to the HOW SUPPLIED section:
`
`BREVIBLOC PREMD(ED INJECTION — DOUBLE STRENGTH
`
`NDC 10019-075-87, 2000 MG — 100 Ml IntraVia Bags
`
`13. The description of the BREVIBLOC INJECTION in the HOW SUPPLIED section has been changed from:
`
`NDC 10019-015-01, 100 mg — 10 mL Ready-to—use Vials, Box of 20
`
`To:
`
`I
`
`NDC 10019-115-01, 100 mg — 10 mL Ready-to-use Vials, Package of 25
`
`Baxter Healthcare Corporation, Anesthesia & Critical Care proposes the following labeling changes to the container
`labeling:
`
`10 mL Ready-to-use Vial Label
`
`1. Changed the NDC number from:
`
`.10019-015-71
`
`To:
`
`.-
`
`10019-115-39.
`
`2. Changed the strength description from:
`
`100 mg/lO mL (10mg/mL)
`
`To:
`
`

`

`100 mg/IO mL
`(10mgmL)
`
`3. Moved the “Rx only” from the third line of text below the lavender band with the drug name to immediately
`below the lavender band with the drug name.
`
`4.
`
`Inserted “ISO-Osmotic” on the line below “FOR INTRAVENOUS USE”
`
`5. Deleted the following:
`
`“ Each mL contains 10 mg Esmolol Hydrochloride and Water for Injection, USP. Buffered with Sodium
`Acetate Trihydrate, USP and Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid
`added to adjust pH to 5.0 (range 4.5-5.5).
`
`6. Moved and changed component code fiom:
`
`“400-409-04” above the bar code
`
`To:
`
`“460-325-00” below the bar code
`
`7. Changed the bar code and corresponding numbers below the bar code.
`
`25 X 10 mL Vials Tray Label
`
`1. Changed the NDC number from:
`
`10019-015-71
`
`To:
`
`10019-115-01
`
`2. Changed the quantity and description from:
`
`20 X 10 mL Ready-to-use Vials
`
`To:
`
`25 X 10 mL Ready-to-use Vials
`
`3. Changed product description fi'om:
`
`lEach mL contains 10 mg Esmolol Hydrochloride and Water for Injection, USP. Bufi‘ered with Sodium
`Acetate Trihydrate, USP and Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid
`added to adjust pH.
`
`To:
`
`Each mL contains 10 mg Esmolol Hydrochloride and 5.9 mg Sodium Chloride, USP in Water for Injection,
`USP. Buffered with Sodium Acetate Trihydrate, USP and Glacial Acetic Acid, USP. Sodium Hydroxide
`and/or Hydrochloric Acid added to adjust pH to 5.0 (range 4.5-5.5).
`
`4. The storage guidelines have been changed from:
`
`

`

`Store at controlled room temperature 15°-30°C (59°-86°F).
`
`To:
`
`Store at 25°C (77°F): Excursions pemiitted to 15°-30°C (59°-86°F).
`
`5.
`
`Inserted “ISO-Osmotic” on the line below “Single dose Vials”
`
`6. Moved manufacturing information from below the line that states “discard unused portion” to below the line
`that states “FOR INTRAVENOUS USE ONLY”.
`
`7. Added the phrase, “registered in the United States Patent and Trademark Office.” following the phrase, “Baxter
`and Brevibloc are trademarks of Baxter International Inc.”
`
`8. Moved and changed the component code from:
`
`400-281-04
`
`To:
`
`460-326-00.
`
`Per the chemistry review, the following change is to be made to the immediate container label:
`
`1. The immediate container label should contain the composition statement as it is in the current container label:
`
`Each mL contains 10 mg Esmolol Hydrochloride and 5.9 mg Sodium Chloride, USP in Water for Injection,
`USP. Buffered with Sodium Acetate Trihydrate, USP and Glacial Acetic Acid, USP. Sodium Hydroxide
`and/or Hydrochloric Acid added to adjust pH to 5.0 (range 4.5-5.5).
`
`Recommendation:
`
`An approval letter should issue be issued for supplement 021 as set forth under 21 CFR 314.70 (b) (3) [Any change
`in labeling].
`
`Melissa Robb, RHPM
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Melissa Robb
`
`2/26/03 09:47:35 AM
`CSO
`
`

`

`
`
`TO (Division/Ofl'ice): Microbiology (HFD-805) for Micro. Consult.
`
`FROM: IV Advani(HFD—110)
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`REQUEST FOR CONSULTATION
`
`
`
`Attn: Dr. Peter Cooney
`
`DATE OF DOCUMENT:
`
`DATE: 12/18 /02
`TYPE or DOCUMENT :
`
`
`1 0/24/02
`
`
`
`Supplements SCF-021
`
`
`Prior Approval Supplement
`
`Premixed Injection,
`
`
`
`
` PRIORITY CONSIDERATION: CLASSIFICATION OF DRUG: DESIRED COMPLETION DATE:
`
` NAME OF DRUGS: Brevibloc
`
`
`January 31,03
`
`
`10 mg/mL in 10 mL in ready
`
`
`to use vials
`
`NAME OF FIRM: Baxter Healthcare Corporation
`
`NEW PROTOCOL
`C1 PROGRESS REPORT
`El NEW CORRESPONDENCE
`D DRUG ADVERTISING
`E] ADVERSE REACTION REPORT .
`B MANUFACTURING CHANGE/ADDITION
`E] MEETING PLANNED BY
`
`REASON FOR REQUEST
`
`I. GENERAL
`
`CI PRE--NDA MEETING
`El END OF PHASE II MEETING
`Cl RESUBMISSION
`C] SAFETY/EFFICACY
`El PAPER NDA
`D CONTROL SUPPLEMENT
`
`v
`
`11. BIOMETRICS
`
`Cl RESPONSE TO DEFICIENCY LETTER
`D FINAL PRINTED LABELING
`El LABELING REVISION
`D ORIGINAL NEW CORRESPONDENCE
`El FORMULATIVE REVIEW
`El OTHER (SPECIFYBELOW:
`
`_
`
`f-
`
`STATISTICAL EVALUATION BRANCH
`
`‘
`
`STATISTICAL APPLICATION BRANCH
`
`Cl TYPE A OR B NDA REVIEW
`El END OF PHASE II MEETING
`El CONTROLLED STUDIES
`U PROTOCOL REVIEW
`
`El OTHER:
`
`.
`
`El CHEMISTRY REVIEW
`El PHARMACOLOGY
`El BIOPHARMACEUTICS
`El OTHER:
`
`Cl DISSOLUTION
`C] BIOAVAILABILTY STUDIES
`D PHASE IV STUDIES
`
`III. BIOPHARMACEUTICS
`
`U DEFICIENCY LETTER RESPONSE
`[3 PROTOCOL-BIOPI-IARMACEUTICS
`D IN-VIVO WAIVER REQUEST
`
`IV. DRUG EXPERIENCE
`
`Cl PHASE IV SURVEILLANCE/EPIDEMIOLOGY PROTOCOL
`El DRUG USE c.g. POPULATION EXPOSURE,
`ASSOCIATED DIAGNOSES
`C] CASE REPORTS OF SPECIFIC REACTIONS (List below)
`El COMPARATIVE RISK ASSESSMENT ON GENERIC DRUG GROUP
`
`El REVIEW OF MARKETING EXPERIENCE, DRUG USE AND SAFETY
`D SUMMARY OF ADVERSE EXPERIENCE
`D POISON RISK ANALYSIS
`
`~—
`
`V. SCIENTIFIC INVESTIGATIONS
`
`Cl CLINICAL
`
`D PRECLINICAL
`
`COMMENTS/SPECIAL INSTRUCTIONS: This supplement is filed for a new formulation with reduced average of active
`ingredient. The vials are
`”—-
`in place of the currently used :
`-—m--
`vials. Micro review for this
`
`‘
`~— change is required.
`
`Thanks.
`
`
`
`SIGNATURE OF REQUESTER: JV Advani XE] HAND
`METHOD OF DELIVERY (Check one):
`i E- MAIL
`
`
`SIGNATURE OF DELIVERER:
` SIGNATURE OF RECEIVER:
`
`
`
`

`

`ll “MCI;
`F
`
`a
`*'
`
`$3“
`
`§ é DEPARTMENTOFHEALTH&HUMANSERVICES
`
`s
`
`”n
`”an
`
`
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA l9-386/S-021
`
`Baxter Healthcare Corporation
`Anesthesia & Critical Care
`
`Attention: Ms. Priya Jambhekar
`Director, Regulatory Affairs
`95 Spring Street
`New Providence, NJ 07974
`
`Dear Ms. Jambhekar:
`
`We have received your supplemental drug application submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act for the following:
`
`Name of Drug Product: Brevibloc (esmolol HCl in sodium chloride) Injection 10 mg/mL in
`10 mL ready-to-use vials
`
`NDA Number: 19-3 86
`
`Supplement number: 021
`
`Date of supplement: October 24, 2002
`
`Date of receipt: October 25, 2002
`
`Unless we notify you within 60 days of the receipt-date that the application is not sufficiently
`complete to permit a substantive review, this application will be filed under section 505(b) of the
`Act on December 24, 2002 in accordance with 21 CFR 314.101(a).
`
`All communications concerning this supplement should be addressed as follows:
`
`US. Postal Service:
`
`Courier/Ovemi
`
`t Mail:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products,
`HFD-l 10
`Attention: Document Room 5002
`5600 Fishers Lane
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products
`HFD-ll 10
`Attention: Document Room 5002
`1451 Rockville Pike
`
`Rockville, Maryland 20857
`
`Rockville, Maryland 20852
`
`

`

`NDA 19-386/8—021
`
`Page 2
`
`If you have any question, please contact:
`
`Ms. Melissa Robb
`
`Regulatory Health Project Manager
`(301) 594-5313
`
`Sincerely,
`/S/
`
`Zelda McDonald
`
`Chief, Project Management Staff
`Division of Cardio-Renal Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`
`
`. This“Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Zelda McDonald
`
`12/13/02 03:24:47 PM
`
`