DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 19-386/S-022
`
`Baxter Healthcare Corporation, Anesthesia & Critical Care
`Attention: Ms. Lidia Mostovy
`95 Spring Street
`New Providence, NJ 07974
`
`Dear Ms. Mostovy:
`
`Please refer to your supplemental new drug application dated January 28, 2003, submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act for Brevibloc Double Strength Injection (esmolol hydrochloride) 20 mg/mL in
`5 mL ready-to-use vials.
`
`This supplemental new drug application provides for the marketing of a new double strength formulation in 5 mL
`vials. This formulation was approved for marketing in 100 mL bags on January 27, 2003 with the approval of S-020.
`
`This supplement proposes the following changes to the package insert:
`
`1. The following changes were made in the title under the BREVIBLOC PREMIXED INJECTION:
`
`a.
`
`(Esmolol Hydrochloride) changed to (Esmolol Hydrochloride in Sodium Chloride)
`
`b. The addition of the following on the next line: 2,500 mg/250 mL (10mg/mL)
`
`c.
`
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride changed to Iso-Osmotic Solution of
`Esmolol Hydrochloride
`
`2. The following changes were made in the title under BREVIBLOC PREMIXED INJECTION DOUBLE
`STRENGTH:
`
`a. The title was changed from BREVIBLOC PREMIXED INJECTION to BREVIBLOC DOUBLE
`STRENGTH PREMIXED INJECTION
`
`b.
`
`(Esmolol Hydrochloride) DOUBLE STRENGTH changed to (Esmolol Hydrochloride in Sodium
`Chloride)
`
`c. The addition of the following on the next line: 2,000mg/100mL (20mg/mL)
`
`d.
`
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride changed to Iso-Osmotic Solution of
`Esmolol Hydrochloride
`
`3. The following changes were made in the title under BREVIBLOC INJECTION:
`
`a.
`
`(Esmolol Hydrochloride) changed to (Esmolol Hydrochloride in Sodium Chloride)
`
`b. The addition of the following on the next line: 100 mg/10 mL (10mg/mL)
`
`c.
`
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride changed to Iso-Osmotic Solution of
`Esmolol Hydrochloride
`
`

`

`NDA 19-386/S-022
`Page 2
`
`4. The addition of the following to the title:
`
`BREVIBLOC DOUBLE STRENGTH INJECTION
`(Esmolol Hydrochloride in Sodium Chloride)
`100 mg/5 mL (20 mg/mL)
`Ready-to-use Vials
`5 mL Vials
`Iso-Osmotic Solution of Esmolol Hydrochloride
`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
`
`5. The following changes were made to the title under BREVIBLOC C0NCENTRATE:
`
`a. The addition of the following line: 2,500 mg/10 mL (250 mg/mL)
`
`6. The following paragraph was added at the end of the Brevibloc Injection subsection of the DESCRIPTION
`section:
`
`100 mg, 5 mL DOUBLE STRENGTH Single Dose Vial – 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).
`
`7. The second sentence in the PRECAUTIONS/General subsection was changed from:
`
`Extravasation of 20mg/mL may lead to a serious local reaction and possible skin necrosis.
`
`To:
`
`With BREVIBLOC CONCENTRATE, extravasation of 20mg/mL or higher may lead to a serious local
`reaction and possible skin necrosis.
`
`8. The third paragraph in the PRECAUTIONS/General subsection was changed from:
`
`Care should be taken in the intravenous administration of BREVIBLOC as sloughing of the skin and necrosis
`have been reported in association with infiltration and extravasation of intravenous infusions.
`
`To:
`
`Care should be taken in the intravenous administration of BREVIBLOC CONCENTRATE as sloughing of
`the skin and necrosis have been reported in association with infiltration and extravasation of intravenous
`infusions.
`
`9. The following sentence was added as the third sentence of the first paragraph of the OVERDOSAGE/Acute
`Toxicity subsection:
`
`Use of BREVIBLOC PREMIXED INJECTION and BREVIBLOC DOUBLE STRENGTH PREMIXED
`INJECTION may reduce the potential for dilution errors.
`
`10. In the DOSAGE AND ADMINISTRATION section, the subsection title has been changed from:
`
`Directions for Use of Brevibloc Premixed Injection and Brevibloc Premixed Injection DOUBLE
`STRENGTH
`
`

`

`NDA 19-386/S-022
`Page 3
`
`To:
`
`Directions for Use of Brevibloc Premixed Injection (10 mg/mL) and Brevibloc DOUBLE STRENGTH
`Premixed Injection (20 mg/mL)
`
`11. The paragraph in the DOSAGE AND ADMINISTRATION/Directions for Use of Brevibloc Premixed
`Injection (10 mg/mL) and Brevibloc DOUBLE STRENGTH Premixed Injection (20 mg/mL) subsection has
`been changed from:
`
`This dosage from 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.
`
`To:
`
`This dosage from is prediluted to 100 or 250 mL to provide a ready-to-use, iso-osmotic solution of either 20
`or 10 mg/mL esmolol hydrochloride in sodium chloride. It is important not to introduce additives to
`BREVIBLOC PREMIXED INJECTION or BREVIBLOC DOUBLE STRENGTH PREMIXED
`INJECTION. See Directions for Use of the Premixed Bag for additional information.
`
`12. The first three sentences of the first paragraph in the DOSAGE AND ADMINISTRATION/Directions for Use
`of the Premixed Bag subsection have been changed from:
`
`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 PVC ports, a medication port and a delivery port. In the case of BREVIBLOC PREMIXED
`INJECTION, the medication port is to be used only for withdrawing an initial bolus from the bag; the
`medication withdrawal port is not intended for repeat bolus administration. Use aseptic technique
`when withdrawing the bolus dose.
`
`To:
`
`Brevibloc Premixed Injection (10 mg/mL) 250 mL IntraVia Bag
`Brevibloc DOUBLE STRENGTH Premixed Injection (20 mg/mL) 100 mL IntraVia Bag
`BREVIBLOC PREMIXED INJECTION (10 mg/mL) and BREVIBLOC DOUBLE STRENGTH
`PREMIXED INJECTION (20 mg/mL) are provided in ready-to-use, non-latex, non-PVC bags with two PVC
`ports, a medication port and a delivery port. The medication port is to be used solely for withdrawing an
`initial bolus from the bag; the medication withdrawal port is not intended for repeat bolus
`administration. The sterility of the premixed bag cannot be assured after repeat withdrawals from the
`bag. The use of aseptic technique is required when withdrawing the bolus dose.
`
`13. The following change was made to the first sentence of the last paragraph 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.
`
`To:
`
`The Brevibloc DOUBLE STRENGTH Premixed Injection contains Esmolol Hydrochloride at a
`concentration of 20 milligrams/mL.
`
`14. 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:
`
`

`

`NDA 19-386/S-022
`Page 4
`
`Do not introduce additives to BREVIBLOC PREMIXED INJECTION or BREVIBLOC PREMIXED
`INJECTION – DOUBLE STRENGTH.
`
`To:
`
`Do not introduce additives to BREVIBLOC PREMIXED INJECTION or BREVIBLOC DOUBLE
`STRENGTH PREMIXED INJECTION.
`
`15. In the DOSAGE AND ADMINISTRATION section, the subsection title has been changed from:
`
`Directions for Use of the 10 mL Ready-to-use Vial (10 milligrams/mL)
`
`To:
`
`Directions for Use of the Ready-to-use Vials
`Brevibloc Injection (10 mg/mL) 10 mL Ready-to-Use Vial
`Brevibloc DOUBLE STRENGTH Injection (20 mg/mL) 5 mL Ready-to-use Vial
`
`16. The first sentence in the DOSAGE AND ADMINISTRATION/Directions for Use of the Ready-to-use Vial
`subsection has been changed from:
`
`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.
`
`To:
`
`This dosage form is prediluted to provide a ready-to-use, iso-osmotic solution of either 10 or 20 mg/mL
`esmolol hydrochloride in sodium chloride recommended for BREVIBLOC intravenous administration.
`
`17. The following paragraph was added at the end of the DOSAGE AND ADMINISTRATION/Directions for Use
`of the Ready-to-use Vial subsection:
`
`The 5 mL DOUBLE STRENGTH Ready-to-use Vial contains Esmolol Hydrochloride at a concentration of
`20 milligrams/mL. When using a 20 milligrams/mL concentration, a loading dose of 0.5 mg/kg infused over
`1 minute period of time, for a 70 kg patient is 1.75 mL.
`
`18. The last two sentences of the DOSAGE AND ADMINISTRATION/Directions for Use of the Brevibloc
`Concentrate 10 mL Ampul (250 milligrams/mL) subsection has been changed from:
`
`Concentrations of BREVIBLOC (Esmolol Hydrochloride) greater than 10 mg/mL are likely to produce
`irritation on continued infusion (see PRECAUTIONS). BREVIBLOC has, however, been well tolerated
`when administered via a central line.
`
`To:
`
`The use of esmolol with propylene glycol has been associated with a higher incidence of venous irritation at
`concentrations greater than 10 mg/mL on continued infusion. Mixed from the ampul at concentrations of
`greater than 10 mg/mL BREVIBLOC has, however, been well tolerated when administered via a central line.
`
`19. The description of the BREVIBLOC INJECTION – DOUBLE STRENGTH in the HOW SUPPLIED section
`has been changed from:
`
`BREVIBLOC PREMIXED INJECTION – DOUBLE STRENGTH
`
`To:
`
`

`

`NDA 19-386/S-022
`Page 5
`
`BREVIBLOC DOUBLE STRENGTH PREMIXED INJECTION
`
`20. The following has been added to the HOW SUPPLIED section:
`
`BREVIBLOC DOUBLE STRENGTH INJECTION
`NDC 10019-085-01, 5 Ml Ready-to-use Vials, Package of 10
`
`Baxter Healthcare Corporation, Anesthesia & Critical Care proposes the container labels to have printing in seafoam
`green as was approved for the DOUBLE STRENGTH formulation in S-020 in 100 mL plastic bags. In the
`submission, there are proposed labels for the both the vial and the vial cartons.
`
`We have completed our review of this application, as amended. This application is approved, effective on the date of
`this letter, for use as recommended in the agreed-upon labeling text and with the minor editorial revisions listed
`below.
`
`1.
`
`2.
`
`In the title under the BREVIBLOC PREMIXED INJECTION, BREVIBLOC PREMIXED INJECTION
`DOUBLE STRENGTH, BREVIBLOC INJECTION and BREVIBLOC DOUBLE STRENGTH INJECTION
`sections, the established name should remain “(Esmolol Hydrochloride)”.
`
`In the title under the BREVIBLOC PREMIXED INJECTION, BREVIBLOC PREMIXED INJECTION
`DOUBLE STRENGTH, BREVIBLOC INJECTION and BREVIBLOC DOUBLE STRENGTH INJECTION
`sections, the description should remain “Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride”.
`
`The final printed labeling (FPL) must be identical, and include the minor editorial revisions indicated, to the submitted
`labeling (package insert and immediate container and carton labels submitted January 28, 2003). These revisions are
`terms of the approval of this application.
`
`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, this submission should be designated "FPL for approved supplement
`NDA 19-386/S-022”. 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:
`
`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:
`
`

`

`NDA 19-386/S-022
`Page 6
`
`Ms. Melissa Robb
`Regulatory Health Project Manager
`(301) 594-5313
`
`Sincerely,
`
`{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
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`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
`5/28/03 04:23:46 PM
`
`