`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`
`
`
`
`
`
`
`
`
`
`NDA 19-386/S-039
`
`Baxter Healthcare Corporation
`Attention: Ivy Bautista
`Director, Regulatory Affairs
`95 Spring Street
`New Providence, NJ 07974
`
`
`Dear Ms. Bautista:
`
`Please refer to your supplemental new drug application (NDA) dated April 24, 2007, submitted under
`section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for Brevibloc (esmolol hydrochloride)
`10 mg/mL, 20 mg/mL and 250 mg/mL IV.
`
`We also refer to your amendment dated September 17, 2007.
`
`This supplemental new drug application provides for the following label revisions in the package insert
`to reflect the discontinuation of the 250 mg/mL ampul concentrate dosage form.
`
`
`1) To delete the following text from the beginning of the package insert just prior to the
`DESCRIPTION section of the labeling:
`
`“BREVIBLOC CONCENTRATE
`
`(Esmolol Hydrochloride)
`
`2,500 mg/10 mL (250 mg/mL) Ampuls for Dilution
`
`10 mL Ampuls
`
`NOT FOR DIRECT INTRAVENOUS INJECTION.
`
`Esmolol Hydrochloride concentration = 250 milligrams/mL (250,000 micrograms/mL)
`
`AMPULS MUST BE DILUTED PRIOR TO INFUSION - SEE DOSAGE AND
`ADMINISTRATION, Directions for Use of the Brevibloc Concentrate 10 mL
`Ampul (250 milligrams/mL).”
`
`2) To delete the following text that comprises the last paragraph in the DESCRIPTION
`section of the labeling:
`
`

`

`NDA 19-386/S-039
`Page 2
`
`
`“Brevibloc Concentrate
`
`BREVIBLOC CONCENTRATE is a clear, colorless to light yellow, sterile,
`nonpyrogenic concentrate.
`
`2500 mg, 10 mL Ampul – Each mL contains 250 mg Esmolol Hydrochloride in 25%
`Propylene Glycol, USP, 25% Alcohol, USP and Water for Injection, USP; buffered with
`17.0 mg Sodium Acetate Trihydrate, USP, and 0.00715 mL Glacial Acetic Acid, USP.
`Sodium Hydroxide and/or Hydrochloric Acid added, as necessary, to adjust pH to 3.5-
`5.5. NOT FOR DIRECT INTRAVENOUS USE - AMPUL MUST BE DILUTED
`PRIOR TO INFUSION. See DOSAGE AND ADMINISTRATION, Directions for
`Use of the Brevibloc Concentrate 10 mL Ampul (250 milligrams/mL).”
`
`3) To delete the following paragraphs from the PRECAUTIONS section, General subsection
`of the labeling:
`
`“Infusion concentrations of 20 mg/mL were associated with more serious venous
`irritation, including thrombophlebitis, than concentrations of 10 mg/mL with
`BREVIBLOC CONCENTRATE, extravasation of 20 mg/mL or higher may lead to a
`serious local reaction and possible skin necrosis. Concentrations greater than 10 mg/mL
`or infusion into small veins or through a butterfly catheter should be avoided.”
`
`and
`
`“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.”
`
`4) To delete the following text from the DOSAGE AND ADMINISTRATION section of the
`labeling:
`
`“Directions for Use of the Brevibloc Concentrate 10 mL Ampul
`(250 milligrams/mL)
`
`THE 2500 mg AMPUL IS NOT FOR DIRECT INTRAVENOUS INJECTION.
`THIS DOSAGE FORM IS A CONCENTRATED, POTENT DRUG WHICH
`MUST BE DILUTED PRIOR TO ITS INFUSION. BREVIBLOC SHOULD NOT
`BE ADMIXED WITH SODIUM BICARBONATE. BREVIBLOC SHOULD NOT
`BE MIXED WITH OTHER DRUGS PRIOR TO DILUTION IN A SUITABLE
`INTRAVENOUS FLUID. (See Compatibility Section below.)
`
`Dilution: Aseptically prepare a 10 mg/mL infusion by adding two 2500 mg ampuls to a
`500 mL container or one 2500 mg ampul to a 250 mL container of a compatible
`intravenous solution listed below. (Remove overage prior to dilution as appropriate.)
`This yields a final concentration of 10 mg/mL. The diluted solution is stable for at least
`24 hours at room temperature. Note: The use of esmolol with propylene glycol has been
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 19-386/S-039
`Page 3
`
`
`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
`REVIBLOC has, however, been well tolerated when administered via
`than 10 mg/mL B
` central vein.”
`
`a
`
`5) To delete the following text from the HOW SUPPLIED section of the labeling:
`
`“BREVIBLOC CONCENTRATE
`
`NDC 10019-025-18, 2500 mg – 10 mL Ampuls for Dilution, Package of 10”
`
`
`We have completed our review of this application, as amended, and it is approved, effective on the
`date of this letter, for use as recommended in the enclosed electronic labeling text. We will transmit
`eling submitted on September 17, 2007 to the National Library of Medicine the SPL version of the lab
`
`r public dissemination.
`fo
`
`th
`If you issue a letter communicating important information about this drug product (i.e., a “Dear Heal
`r), we request that you submit a copy of the letter to this NDA and a copy to
`Care Professional” lette
`e following address:
`th
`
`
`
`
`
`
`
`Marketing the product with labeling that is not iden
`roduct misbranded and an unapproved new drug.
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEDWATCH
`Food and Drug Administrat
`5515 Security Lane
`HFD-001, Suite 5100
`Rockville, MD 20852
`
`ion
`
`tical to the approved labeling text may render the
`
`e remind you that y
`14.80 and 314.81).
`
`ou must comply with reporting requirements for an approved NDA (21 CFR
`
`p W
`
`3 I
`
`ase call Dan Brum, Pharm.D., MBA, Regulatory Health Project
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`f you have any questions, ple
`anager, at (301)796-0578.
`
`M
`
`
`
`
`
`

`

`NDA 19-386/S-039
`Page 4
`
`
`Sincerely,
`
`{See appended electronic signature
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Prod
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
` page}
`
`ucts
`
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Norman Stockbridge
`11/6/2007 05:54:58 PM
`
`