DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`Food and Drug Administration
`Rockville, MD 20857
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`NDAs 19-386/S-019 & S-020
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`Baxter Healthcare Corporation, Anesthesia & Critical Care
`Attention: Ms. Priya Jambhekar
`95 Spring Street
`New Providence, NJ 07974
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`Dear Ms. Jambhekar:
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`Please refer to your supplemental new drug applications dated September 30, 2002, submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act for Brevibloc Premixed Injection (esmolol
`hydrochloride) 10 mg/mL in 250mL Bags (S-019) and Brevibloc Double Strength Premixed Injection
`(esmolol hydrochloride) 20mg/mL in 100mL Containers (S-020).
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`We acknowledge receipt of your submission dated January 13, 2003.
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`These supplemental new drug applications provide for changes to the currently approved NDA 19-386.
`Supplement 019 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:
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`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.
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`Supplement 019 includes the reformulation of the Premixed Injection to reduce overage of the active from
`10% to 4%. In addition, it includes a change in the text on the bags from red to lavender. Supplement 020 is
`to market a new formulation, Brevibloc Double Strength Premixed Injection in a ready-to-use 100mL PL-
`2084 plastic bag with dual ports, containing 20 mg/mL concentration of esmolol HCl.
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`These supplements propose the following changes to the package insert:
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`1. The addition of the following to the title of the package insert:
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`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.
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`

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`Esmolol Hydrochloride concentration = 20 milligrams/mL (20,000 micrograms/mL)
`Single Patient Use Only
`No Preservatives Added
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`NDA 19-386/S-019 & S-020
`Page 2
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`2. The addition of the following line to the title under the BREVIBLOC INJECTION, Ready-to-use
`Vials, 10mL Vials:
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`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride
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`3. The addition of the following paragraph at the end of the DESCRIPTION section, Brevibloc Premixed
`Injection subsection:
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`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 312mOsmol/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.
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`4. The DESCRIPTION/Brevibloc Injection subsection has been changed from:
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`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.
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`To:
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`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).
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`5. Under the DOSAGE AND ADMINISTRATION section, the subsection heading has been changed
`from:
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`Directions for Use of Brevibloc Premixed Injection
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`To:
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`Directions for Use of Brevibloc Premixed Injection and Brevibloc Premixed Injection
`DOUBLE STRENGTH
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`6. Under the DOSAGE AND ADMINISTRATION/Directions for Use of Brevibloc Premixed Injection
`and Brevibloc Premixed Injection DOUBLE STRENGTH subsection, the paragraph has been
`changed from:
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`NDA 19-386/S-019 & S-020
`Page 3
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`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.
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`To:
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`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.
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`7. Under the DOSAGE AND ADMINISTRATION/Directions for Use of the Premixed Bag subsection,
`the first sentence has been changed from:
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`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.
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`To:
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` 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.
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`8. The following paragraph was added to the end of the DOSAGE AND ADMINISTRATION/Directions
`for Use of the Premixed Bag subsection:
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`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.
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`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.
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`10. 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:
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`Do not introduce additives to BREVIBLOC PREMIXED INJECTION.
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`To:
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`Do not introduce additives to BREVIBLOC PREMIXED INJECTION or BREVIBLOC
`PREMIXED INJECTION – DOUBLE STRENGTH.
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`11. 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 from:
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`This dosage form is prediluted to provide a ready to use 10mg/mL concentration recommended for
`BREVIBLOC intravenous administration.
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`To:
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`NDA 19-386/S-019 & S-020
`Page 4
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`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.
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`12. The following has been added to the HOW SUPPLIED section:
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`13. The description of the BREVIBLOC INJECTION in the HOW SUPPLIED section has been changed
`from:
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`BREVIBLOC PREMIXED INJECTION – DOUBLE STRENGTH
`NDC 10019-075-87, 2000 MG – 100 Ml IntraVia Bags
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`NDC 10019-015-01, 100 mg – 10 mL Ready-to-use Vials, Box of 20
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`To:
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`NDC 10019-115-01, 100 mg – 10 mL Ready-to-use Vials, Package of 25
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`NDA 19-386/S-019 proposes the following changes to the container labeling:
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`Immediate Plastic Bag Labeling
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`1. The color of the text of the Lot/Exp, NDC number, Product Name, and strength has been changed from
`bright red to lavender.
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`Foil Pouch Labeling
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`1. The manufacturing code and product code located on the bottom right hand corner above the number for
`product inquiries have been changed from:
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`2J1404
`460-250-00
`7-7-10-978
`2000/8
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`To:
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`2J1415
`460-370-00
`7-7-31-553
`2000/8
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`2. The addition of text on the back of the foil pouch including the product name and strength in lavender.
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`NDA 19-386/S-020 proposes the following new container labeling, as compared to the current single
`strength labeling:
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`Transfer Label
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`1. The product name will appear in sea foam green as opposed to lavender.
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`2. The potency will read 20mg/mL instead of 10mg mL.
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`3. The NDC code will be 460-372-00 instead of 460-268-00.
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`NDA 19-386/S-019 & S-020
`Page 5
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`4. The product name will read Brevibloc DOUBLE STRENGTH Premixed Injection rather than Brevibloc
`Premixed Injection.
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`5. The manufacture code will be 7-00-00-000 instead of 7-09-18-925.
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`20mg/mL in 100 mL Bag
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`1. The product name will appear in sea foam green as opposed to bright red.
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`2. The NDC code will read 10019-075-87 instead of 10019-055-61.
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`3. The product name with read Brevibloc DOUBLE STRENGTH Premixed Injection rather than Brevibloc
`Premixed Injection.
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`4. The strength will read 2,000mg/100mL (20mg/mL) not 2,500mg/250mL (10mg/mL).
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`5. The contents will read “Each mL contains 20mg esmolol hydrochloride, 4.1 mg sodium chloride USP in
`water for injection USP. Buffered with 2.8 mg sodium acetate trihydrate USP and 0.546 mg glacial
`acetic acid USP pH adjusted with sodium hydroxide and/or hydrochloric acid pH 5.0 (4.5-5.5) Sterile
`nonpyrogenic”. This is instead of 10mg esmolol hydrochloride, 5.9 mg sodium chloride USP as in the
`single strength; all other wording is unchanged.
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`6. The component code will be 460-324-00 instead of 460-249-00.
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`7. The manufacturing code, internal tracking number will be 2J1413 instead of 2J1404.
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`Foil Pouch Labeling
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`1. The product name will appear in sea foam green as opposed to lavender.
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`2. The NDC code will read 10019-075-87 instead of 10019-055-61.
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`3. The product name with read Brevibloc DOUBLE STRENGTH Premixed Injection rather than Brevibloc
`Premixed Injection.
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`4. The strength will read 2,000mg/100mL (20mg/mL) instead of 2,500mg/250mL (10mg/mL).
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`5. The contents will read “Each mL contains 20mg esmolol hydrochloride, 4.1 mg sodium chloride USP in
`water for injection USP. Buffered with 2.8 mg sodium acetate trihydrate USP and 0.546 mg glacial
`acetic acid USP pH adjusted with sodium hydroxide and/or hydrochloric acid pH 5.0 (4.5-5.5) Sterile
`nonpyrogenic”. This is instead of 10mg esmolol hydrochloride, 5.9 mg sodium chloride USP as in the
`single strength; all other wording is unchanged.
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`6. The component code has changed to 2J1413; 460-371-00; 7-7-31-552 instead of 2J1404; 460-250-00; 7-
`7-10-978.
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`7. A product identification is to be added to the back of the pouch in seafoam green with product name and
`strength.
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`We have completed the review of these applications, as amended, and have concluded that adequate
`information has been presented to demonstrate that the drug products are safe and effective for use as
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`

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`NDA 19-386/S-019 & S-020
`Page 6
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`recommended in the proposed draft labeling included in your September 30, 2002 submission. Accordingly,
`these applications are approved effective on the date of this letter.
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`The final printed labeling (FPL) must be identical to the submitted labeling (package insert and immediate
`container and carton labels submitted September 30, 2002).
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`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 after it is printed. Please individually mount ten of the
`copies on heavy-weight paper or similar material. For administrative purposes, these submissions should be
`designated "FPL for approved supplement NDA 19-386/S-019, S-020”. Approval of these submissions by
`FDA is not required before the labeling is used.
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`In addition, submit three copies of the introductory promotional materials that you propose to use for these
`products. 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:
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`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
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`5600 Fishers Lane
`Rockville, MD 20857
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`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:
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80
`and 314.81).
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`If you have any questions, please call:
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`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
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`Ms. Melissa Robb
`Regulatory Health Project Manager
`(301) 594-5313
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`Sincerely,
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`{See appended electronic signature page}
`
`Douglas C. Throckmorton, M.D.
`Director
`Division of Cardio-Renal Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Doug Throckmorton
`1/27/03 02:22:48 PM
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