CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`‘ APPLICATION NUMBER
`
`19-386/5-021
`
`Approval Letter(s)
`
`

`

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`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 19-386/8-021
`
`Baxter Healthcare Corporation, Anesthesia & Critical Care
`Attention: Ms. Priya Jambhekar
`95 Spring Street
`New Providence, NJ 07974
`
`Dear Ms. Jambhekar:
`
`Please refer to your supplemental new drug application dated October 24, 2002, submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act for Brevibloc Injection (esmolol hydrochloride) 10 mg/mL in 10 mL ready to
`use vials.
`
`We acknowledge receipt of your submission dated January 13, 2003.
`
`This supplemental new drug application provides for a new isotonic formulation of Brevibloc Injection 10 mg/mL in 10
`mL vials. This supplement also 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, S-018, for
`Brevibloc Premixed Injection 10mg/mL packaged in 250 mL Bags on February 16, 2001. The commitment was 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 that the
`supplement(s) will be submitted.
`
`This supplement proposes the following 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 of the following paragraph at the end of the DESCRIPTION section, Brevibloc Premixed Injection
`subsection:
`
`

`

`NDA l9-386/S-021
`
`Page 2
`
`2000 mg, 100 mL Single Use Premixed Bag DOUBLE STRENGTH - Each mL contains 20 mg Bsmolol
`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 312 mOsmol/L. The 100
`mL bag is non-latex, non-PVCIntraVia bag with dual PVC ports. The IntraVia bag is manufactured fi'om 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/Brevibloe Injection subsection has been changed fi‘om:
`
`BREVIBLOC INJECTION is a clear, colorless to light yellow, sterile, nonpyrogenic solution.
`100 mg, 10 mL Single Dose Vial — Each mL contains 10 mg Bsmolol 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 Bsmolol 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. Under the DOSAGE AND ADMINISTRATION section, the subsection heading has been changed from:
`
`Directions for Use of Brevibloe Premixed Injection
`
`To:
`
`Directions for Use of Brevibloe Premixed Injection and Brevibloe Premixed Injection DOUBLE
`STRENGTH
`
`6. Under the DOSAGE AND ADMINISTRATION/Directions for Use of Brevibloe Premixed Injection and
`Brevibloe 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:
`
`a
`
`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 PREMD<ED
`INJECTION orBREVIBLOC PREMIXED INJECTION DOUBLE STRENGTH. See Directions for Use of
`
`the Premixed Bag for additional information.
`
`7. Under the DOSAGE AND ADMINISTRATION/Directions for Use of the Premixed Bag subsection, the first
`sentence has been changed fiom:
`
`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:
`
`

`

`NDA 19-386/S-021
`
`Page 3
`
`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/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.
`
`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.
`
`In the DOSAGE AND ADMINISTRATION/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.
`
`The first sentence under the DOSAGE AND ADMINISTRATION/Directions for Use of the 10 mL Ready-to-
`use Vial (10 milligrams/mL) subsection has been changed flow
`
`This dosage form is prediluted to provide a ready to use 10mg/mL concentration recommended for
`BREVIBLOC intravenous administration.
`
`To:
`
`This dosage form is prediluted to provide a ready-to-use, iso—osmotic solution cf 10mg/mL esmolol
`hydrochloride in sodium chloride recommended for BREVIBLOC intravenous administration.
`
`The following has been added to the HOW SUPPLIED section:
`
`BREVIBLOC PREMIXED INJECTION — DOUBLE STRENGTH
`
`NDC 10019-075—87, 2000 MG — 100 Ml IntraVia Bags
`
`The description of the BREVIBLOC INJECTION in the HOW SUPPLIED section has been changed from:
`
`10.
`
`11.
`
`12.
`
`13.
`
`NDC 10019—01 5-01, 100 mg -— 10 mL Ready-to—use Vials, Box of 20
`
`To:
`
`- NDC 10019-115-01, 100 mg — 10 mL Ready-to—use Vials, Package of 25
`
`This supplement proposes the following changes to the container labeling:
`
`10 mL Ready-to—use Vial Label
`
`1. Changed the NDC number from:
`
`10019-015-71
`
`

`

`NDA 19-386/S-021
`
`Page 4
`
`To:
`
`10019-115-39.
`
`2. Changed the strength description from:
`
`100 mg/lO mL (10mg/mL)
`
`To:
`
`100 mg/lO mL
`(10mg/mL)
`
`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 fi'om:
`
`“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:
`
`10019-1 15-01.
`
`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 from:
`
`

`

`NDA 19-386/S-021
`
`Page 5
`
`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.
`L
`
`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
`
`We have completed the review of this application, as amended, and have concluded that adequate information has been
`presented to demonstrate that the drug products are safe and effective for use as recommended in the proposed drafl
`labeling included in your October 24, 2002 submission. Accordingly, this application is approved effective on the date
`of this letter.
`
`The final printed labeling (FPL) must be identical to the submitted labeling (package insert and immediate container and
`carton labels submitted October 24, 2002) with the following change 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).
`
`Please submit the FPL electronically according to the guidance for industry titled Providing Regulatory Submissions in
`Electronic Format — NDA. Alternatively, you may submit 20 paper copies of the FPL as soon as it is available, in no
`case more than 30 days afier it is printed. Please individually mount ten of the copies on heavy-weight paper or similar
`material. For administrative purposes, this submission should be designated "FPL for approved supplement NDA l9-
`386/S-021”. Approval of this submission by FDA is not required before the labeling is used.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for this product.
`Submit all proposed materials in draft or mock-up form, not final print. Send one copy to the Division of Cardio-Renal
`Drug Products and two copies of both the promotional materials and the package inserts directly to:
`1
`
`

`

`NDA 19-386/S-021
`
`Page 6
`
`Division of Drug Marketing, Advertising, and Communications, HFD—42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`_
`
`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health Care
`Professional” letter), 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 reporting requirements for an approved NDA (21 CFR 314.80 and 314.81).
`
`If you have any questions, please call:
`
`Ms. Melissa Robb
`
`Regulatory Health Project Manager
`(301) 594-5313
`
`Sincerely,
`
`{See atfi‘d electronic signature page}
`
`/
`
`Douglas C. Throckmorton, MD.
`Director
`
`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.
`
`Doug Throckmorton
`2/25/03 09:03:24 AM
`
`