CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER(S)
`
`NDA 1'9-386/5-022
`
`- Trade Name:_
`
`Brevibloc
`
`Generic Name(s):
`'
`
`(.EsmOlOl hydrochloride in sodium
`chloride )
`-
`
`Sponsor:
`Agent:
`
`Baxter-‘Healthcalre Corporation
`‘
`
`Approval Date: 7
`
`_ May 28, 2003
`
`Indication: Short—Term COntrOl Of_'heart rate in patients
`with abnormally fast heart rhythmslsuch as artrial fibrillation,
`atrial flutter or sinus tachycardia.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`APPLICATION NUMBER:
`flflfib :/ 8-021";
`
`CONTENTS
`
`'
`
`; Rev1e—s'lMOnnatni0 Iluncded-in this NDA Review. '
`
`
`
`'
`
`
`' A‘s _' rbval Letter
`I "A u - rovable Letter
`Final-Printed Labélin_
`MédicalReview’G)
`’
`. Chemistr Review(s)
`
`. EA/FONSI
`. Pharmacolo _- Review(s)
`f Statistical ReVieW(S')-.
`_
`,Mi‘cmbi'ol(1'v_ReYieW(s). -
`
`, BioresearchMonitorin- '
`
`
`
`’
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 19-386/5-022
`
`Approval Letter(s)
`
`

`

`
`
`I
`
`1: DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`PUb'lC Health service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 19—386/8—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(h) of the
`Federal Food, Drug, and Cosmetic Act for Brevibloc Double Strength Injection (esmolol hydrochloride) 20 mg/mL1n
`.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 8—020.
`
`v
`
`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 nig/250 mL (lOmg/mL)
`
`c.
`
`ISO-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride changed to ISO—Osmotic Solution of
`'Esmolol Hydrochloride
`2. The following changes were madein the title underBREVIBLOC 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 Hydrochloride1n Sodium
`
`_
`
`. Chloride)
`
`.
`
`c. The addition of the following on the next line: 2,000rng/100mL (20mg/mL)
`
`’d-.
`
`Iso-Osmotic Solution ofEsmolol Hydrochloride1n Sodium Chloride changed to Iso-Osmot—ic Solution of
`Esmolol Hydrochloride
`'
`
`3. The following changes were made in the title under BREVIBLOC INJECTION:
`
`a.
`
`b.-
`
`c.
`
`(.Esmolol Hydrochloride) changed to (Esmolol Hydrochloride in Sodium Chloride)
`
`.The addition of the following on the next line: ’100 mg/10 mL (lOmg/mL)_
`
`150—Osmotic Solution ofEsmo‘lol Hydrochloride1n SodiumChloride Changed to Iso-Osmotic Solution of
`Esmolol Hydrochloride
`
`

`

`NDA 19—386/8-022
`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 V_ials
`
`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/mm
`Single Patient Use Only
`No Preservatives Added
`
`5. The following changes were made to the title under- BREVIBLOC CONCENTRATE:
`
`a. The addition of the fbllowing 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
`Hydrochlofide, 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:
`
`Extravas'ation of 20mg/mL may lead to a serious local reaction and possible skin necrosis.
`
`To:
`
`With BREVIBLOC CONCENTRATE, extravasation of20mg/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 iri the intravenOus adrnini'stratiOn of BREVIB‘LOC CONCENTRATE as sloughing of _
`the skin and necrosis. have been reported in‘assoc-iation with infiltratiOn and extravasation of- intravenous
`‘
`infusions.
`>
`
`'
`
`9. The following sentence was added as the third sentence ofthe first paragraph of theOVERDOSAGE/Acute
`Toxicity subsection:
`..
`
`'
`
`Use ofBREV-IBLOCPREMIXED 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 Inject-ion DOUBLE
`STRENGTH
`
`

`

`NDA 19—386/S»022
`
`- Page 3
`
`To:
`
`. Directions for Use of Brevibloc Premixed Injection (10 mg/mL) andBrevibloc DOUBLE STRENGTH
`.‘.
`Premixed Injection (20 mg/mL)
`
`I I 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 of20 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 infoxmation.
`
`12. The first three sentences of the first paragraphin 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 port15 to be used only for withdrawing an initial bolus from the bag; the
`medication withdrawal port'15 not intended for repeat bolus administration. Use aseptic technique
`when withdrawing the bolus dose.
`'
`
`To:
`
`\
`Brevibloc Premixed Injection (1'0 mg/mrL)-250 m'L IntraVia Bag
`Brevibloc DOUBLE STRENGTH Premixed Injection (20 mg/mL) 1-00 mL In'traVia Bag
`BREVIBLOC PREMIXED INJECTION (10 mg/mL) and BREVIBLOC DOUBLE STRENGTH
`_ PREMIXED INJECTION (20 mglmL) are providedin ready—to——use_, non-latex, nan-PVC bags with two PVC
`ports, a medication port and a delivery port. The medication portIS to be-used-solely for withdrawing an
`initial bolus from the bag; the medication withdrawal port15 not intended I01- repeat bolus
`-
`’
`' administration. The sterility-of the premixed bag cannot be ass'11r-ed afterrepeat withdrawals from the
`.b..ag The use or aseptic technique15required when withdrawing the bolus dose.
`13. The following change was made to the first sentence ofthe last'paragraph‘oflftheDOSAGE AND- .
`. ADMINISTRATION-[Directions for Use of the Premixed Bag subSection:
`-
`
`The Brevibioc Premixed Injection DOUBLE STRENGTH Contains Esmoloi Hydrochlorxde 'at a
`concentrationof 20 milligrams/mL.
`'
`
`To:
`
`The Brevibloc DOUBLE STRENGTH Premixed Injection contains .Esmolol Hydrochlon'de- at a
`concentration of 20 milligrams/mL.
`
`14. In the DOSAGE AND ADMINISTRATION/Directions for Use ofthe Premixed Bag subsection, the IaSt
`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 Vi'al (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 lOmg’JmL 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/Directi‘ons for Use
`of the Ready—to-use Vialsubsection:
`
`The 5 mL DOUBLE STRENGTH Ready-to—use Vial contains .Esmolol Hydrochloride at a concentration of
`20 milligrams/mL. When using a 20milligrams/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.
`
`1.8. The last two sentences ofthe DOSAGE AND ADMINISTRATION/Directions for Use ofthe Br-e'vibloe
`‘
`Concentrate 111 mL Ampul (250 milligrams/mL) subsection has been changedfrom:
`
`- Concentrationsof BREVIBLOC (EsmOlol Hydrochloride) greaterthan 10 mg/r'riL 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.esrnolol Withpropylene glycol has "been" associated with a higher incidence elf-venous imitation 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—O22
`
`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 MI 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 vialcartons.
`
`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.
`
`I.
`
`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, 20,03). 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
`' NDA19-386/S-022”. Approval ofthis submission by FDA is not required before the labeling is used.
`
`'
`
`In addition, su‘brnit three copies of the introductory promotional-materials that you propose to use for this product.
`Subr‘nit 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 Fisher's Lane '
`'FRockville, MD 208-57
`
`'_ Ifyou issue a letter cormnunicating important information about this drug product (i.e.', a “Dear Health Care
`. Professional" letter), .we request that you submita copy of the letterto this NDA and a copy to the following address:
`NIBDWATCH, HF—2
`(FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`We remind you that you must comply With reportingrequirements for an approved NDA (21 CFR 314.80 and
`3 14. 8 l).
`‘
`.
`
`. Ifyou have any questions, pleasecallz -.
`
`

`

`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, MD.
`Director
`
`Division of Cardio—Renal Drug Products
`Office ofDrug Evaluation I
`Center for Drug Evaltiation 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
`5/28/03 04:23:46 PM
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`_
`
`APPLICATION NUMBER
`
`NDA 19-386/5-022
`
`Chemistry Revi.ew(s)
`
`

`

`NDA 19—3 86/022
`
`'
`
`1
`
`CHEMIST‘S REVIEW
`
`1. ORGANIZATION
`HFD—l 10
`
`2. NBA Number
`19—386
`
`-
`
`3. Name and Address of Applicant (City & State)
`Baxter Phannaceutical Products Inc.
`95 Spring Street
`New Providence, NJ 07974
`
`.
`
`4. Supplement(s) _
`- Number(s)
`SCM/OZZ
`
`-
`
`Date(s)
`01/28/03
`
`_lass vials. 9. Pharmacological Category
`
`5. Drug Name
`Brevibloc
`
`6. Nonproprietary Name
`Esmolol HCl
`
`7. Amendments & Other (reports,
`etc) Dates
`
`8. Supplement Pro'vides For:
`New product formulation double strength (20 mg/mL) Premixed
`Injection (esmolol HCl in sodium chloride) in a ready-to-use 5 mL
`
`Anti—adreneric
`.
`12. Dosage Form(s)
`Intravenous injection
`
`: recetor
`
`»
`
`'
`
`‘
`
`10. How Dispensed
`Elm Doro
`_
`Potency(ies)
`13.
`20 mg/mL in 5 mL vial
`total amount 100 m_
`
`11.
`
`' Related IND(s)/
`‘
`NDA(s)/DMF(s)
`DMFS—tm
`'_’._,
`'
`
`'
`
`14. Chemical Name and Structure '
`(i- ) methyl p—[Z—hydrOXy—(isopropylamino)pr0poxy]
`hydrocinnamate hydrochloride
`
`.
`
`Molecular weight: 331.8
`
`. Empirical formula:
`
`C“; H25 N04 .HCI
`
`15. Records/Reports
`Current
`EYes DNo
`
`Reviewed
`EYes DNo '
`
`16. Comments:
`
`This double strength (DS) 20 mg/mL qualitative formulation is same as the approved (single Strength [88])
`10 mymL Brevibloc Premixed injection in 5 mL vial, "including the proposed reduction in the overage of
`esmololto 4% (refer 8-019 dated 9/30/02). Firm has provided 3 mOnths stability data in the ready to use
`fonnulation in the 5 mL containers. Firm has also provided the manufacturing formula'and executed batch
`records for double strength 20 mg/mL, in 5 mL vial. Firm has provided the revised labeling with relevant
`changes. Firm has provided the Environment Assessment Categorical Exclusion Certification.
`Cont’d
`
`"
`
`17. Conclusions and Recommendations
`.This PA. supplement may be approved from the standpoint of chemistry, microbiology, and drafi labeling.
`Refer microbiology and draft labeling reviev'vs filed with this Supplement. There are no new establishments
`sites used for manufacturing this new Brevibloc double strength premixed'1nj ection.
`.
`The need for this double strength 20 mg/mL, in addition to the sponsor’s eXisting single strength (SS)
`10 m- mL formulation was also recommended b the A-enc on Jan.05 2001
`REVIEWER
`
`18'.
`
`Name
`JV Advani
`
`Signature
`
`*
`
`.
`
`-
`
`Date Completed
`May 05, 2003
`
`

`

`I _U(___._ Pa:€(3)_Wit
`
`seld f
`
`—><— § 552(b)(4) Trae Secret / confidential
`
`'
`
`—.— § 552(b)(5) Ddibemtive PFOCQSS _
`
`._..._ § 5-52<bh><4)mftLabe1m ?
`
`;
`
`I
`
`"
`
`»
`
`T
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`_.___...._.__...__....._,._______
`
`J. V. Advani
`
`5/22/03 08:25:25 AM
`CHEMIST
`
`Kasturi Srinivasachar
`
`5/22/03 05:29:24 PM
`CHEMIST
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 19-386/S-022
`
`Microbiology Review(_s)
`
`

`

`Product Quality Microbiology Review
`
`Review for HFD- 110
`May 22, 2003
`
`NBA: 19-386/SCM-022
`
`Drug Product Name
`Proprietary: Brevibloc Double Strength Injection
`Non-proprietary: esmolol HCl in sodium chloride
`Drug Product Classification: for treatmentof tachycardia
`
`Review Number: 1
`
`' Subject of this Review
`Submission Date: January 28,2003
`Receipt Date:
`Consult Date: January 31, 2003
`Date Assigned for Review: March 24, 2003
`
`Submission History (for amendments only):
`
`Applicant/Sponsor
`Name:
`- Baxter Healthcare Corporation
`Address: 95' Spring Street
`' New Providence, NJ 07974
`Representative:
`Priya Jambhekar, Dir. Reg. Affairs
`Telephone:
`(908) 286—7215
`
`Name of Reviewer:
`
`James L. McVey
`
`
`Conclusion: This supplemental application to .add
`.5»mL
`- vials of20 mg/mL Brevibloc to the current production done at-
`is recommended for approval from a product quality
`microbiology perspective
`
`

`

`Microbiology Review #1
`NDA 19—386/ SCM—022
`
`
`Product Quality Microbiology Data Sheet
`
`A.
`
`1.
`
`2.
`
`TYPE OF SUPPLEMENT: Prior Approval
`
`SUPPLEMENT PROVIDES FOR: A new double strength formulation
`(20 mg/mL). The double strength formulation in 5 mL vials is identical to
`the formulation approved on January 27, 2003 for Brevibloc double
`strength in 100 mL bags.
`
`3.
`
`MANUFACTURING SITE: -'
`
`
`
`
`
`4.
`
`5.
`
`6.
`
`DOSAGE FORM, ROUTE OF ADMINISTRATION AND
`STRENGTH/POTENCY: 20 mg/mL in a 5 mL ready—to—use vial for IV
`administration.
`
`METHOD(S) OF STERILIZATION: ’EK—a
`
`PHARMACOLOGICAL CATEGORY: beta blocker
`
`B.
`
`C.
`
`SUPPORTING/RELATED DOCUNIENTS:
`
`
`REMARKS:
`
`
`filename: l9386s22r1
`
`Page 2 of 8
`
`

`

`Microbiology Review #1
`NDA’ 19-3 86/ SCM-022
`
`
`Executive Summagy
`
`I.
`
`Recommendations
`
`A.
`
`B.
`
`Recommendation on Approvability -— Recommended for
`approval.
`
`Recommendations on Phase 4 Commitments and/or
`Agreements! if Approi’able —— None. The applicant has committed
`to establishing holding times during initial production.
`
`H.
`
`Summary of Microbiology Assessments
`
`A.
`
`Brief Description of the Manufacturing Processes that relate to
`
`Product Quality Microbiology —; —
`
`
`
`B.
`
`C.
`
`Brief Description of Microbiology Deficiencies — None.
`
`Assessment of Risk Due to Microbiology Deficiencies -
`Minimal risk to patient health is perceived from implementation of
`this supplement.
`
`III.
`
`Administrative
`
`A.
`
`Reviewer's Signature
`
`- B.
`
`Endorsement Block
`Review Microbiologist. J.L. McVey
`Microbiology Supervisor. P.H. Cobney
`
`'
`
`C.
`
`' CC'Block
`cc:
`
`DFS
`
`HFD— 805/McVey/19386522r1
`
`.
`
`I
`
`I
`
`I
`
`I
`
`r
`
`-
`
`Page 3 of 8
`
`

`

`
`
` "\ H Page(s) Withheld
`
`-_.>_<___ § 552(b)-(4) Trad-e Secret / confidential
`
`¥§ 552'(b).(5) Deliberative PrO-C'esvs .
`
`_
`
`.-
`
`________ § 552(b)(4) DraftLabelin 7
`
`_
`
`"
`
`

`

`NDA 19-386/ SCM-022
`
`Microbiology Review #1
`
`___________________________________
`
`MPH—hie
`
`F.3. Microbial. Limits Testing — NA.
`
`- G.
`
`LABELING .
`
`H.
`
`LIST-OF MICROBIOLOGY DEFICIENCIES AND
`COMMENTS: None.
`
`Page 8 of 8
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`James McVey
`5/22/03 10 52 23 AM
`MICROBIOLOGIST
`
`Peter Cooney
`5/23/03 01:00:31 PM
`MICROBIOLOGIST
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA ,19-386/5-022'
`
`Administrative] Correspondence
`
`

`

`7 RI-IPM Review of Draft Labeling
`NDA 19-386/S-022
`
`Date of Submissions:
`Date of Review:
`Applicant Name:
`Product Names:
`
`January 30, 2003
`February 7, 2003
`Baxter Healthcare Corporation, Anesthesia & Critical Care
`Brevibloc Double Strength Injection, 20 mg/mL, in SmL ready-to-use vials
`
`Evaluation:
`
`This submission is to market a Double Strength formulation in 5 mL vials, identical to the formulation that was
`approved on January 27, 2003 for Brevibloc Double Strength bags, packaged in 100mL bags.
`
`Baxter Healthcare Corporation, Anesthesia & Critical Care proposes the following labeling changes to the package
`insert:
`
`. l. 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 rug/250 mL (lOmg/mL)
`
`c.
`
`ISO-Osmotic Solution ofEsmolol 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.ofEsmolol 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.
`
`b.
`
`(Esmolol Hydrochloride) changed to (Esmolol Hydrochloride in Sodium Chloride)
`
`i The addition ofthe following on the next line: 100 mg!10_mL (lOmg/mL)
`
`c.
`
`ISO-Osmotic Solution ofEsmolol Hydrochloride in Sodium Chloride changed to Isa-Osmotic Solution
`of Esmolol Hydrochloride
`'
`-
`4. The addition ofthe 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 ofEsmolol Hydrochloride
`- For Intravenous Use
`Can be used for direct intravenous use.
`
`

`

`Esmolol Hydrochloride concentration= 20 milligrams/mi. (20,000 micrograms/mL)
`Single Patient Use Only
`No Preservatives Added
`
`5.. The following changes were made to the title under BREVIBLOC CONCENTRATE:
`
`a. The addition ofthe following line: 2,560 my10 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 ZOmymL 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 ofthe 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 ofthe OVERDOSAGElAcute
`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 ADMINISTRATIONsection, the subsection title has been changed from:
`
`Directions for Use of Brevibloc Premixed Injectidn and Brevibloc Premixed Injection DOUBLE
`STRENGTH
`
`To:
`
`Directions for Use ofBrevibloc Premixed Injection (10 mg/mL) and Brevibloc DOUBLE
`STRENGTH Premixed Injection (20 mg/mL)
`
`1 l. The paragraph in theDOSAGE 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 fi'om is prediluted to 100 or 250 mL to provide a ready—to-use, iso-osmotic solution of20 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 fi'om 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 ofthe 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 mglmL) 250 mL IntraVia Bag
`Brevibloc DOUBLE STRENGTH Premixed Injection (20 mglmL) 100 mL IntraVia Bag
`BREVIBLOC PREMIXED INJECTION (10 mg/mL) and BREVIBLOC DOUBLE STRENGTH
`PREMD(ED 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 ofthe 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.
`
`I To:
`
`The Brevibloc DOUBLE STRENGTHPremixed Injection contains Esmolol Hydrochloride at a
`concentration of20 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:
`
`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 ADMINISTRATIONVsection, 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 ngmL) 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 ofthe Ready-to-use Vial
`subsection has been changed fi'om:
`
`(
`
`.
`
`This dosage form is prediluted to provide a ready-to—use, iso-osmotic solution of lOmg/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 Vialsubsection:
`
`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 mgr/kg infiised
`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/mLBREVIBLOC has, however, been well tolerated when administered via a central
`line.
`
`19. The description of the BREVIBLOC INJECTION— DOUBLE STRENGTH1n the HOW SUPPLIED section _
`has been changed fi‘om:
`
`BREVIBLOC PREIVHXED INJECTION —— DOUBLE STRENGTH
`
`To:
`,
`BREVIBLOC DOUBLE STRENGTH PRENIIXED 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 8-020 in 100 mL plastic bags.
`In the
`submission, there are proposed labels for the both the vial and the vial cartons.
`
`According to a review by Dr. Advani on May 22, 2003, this supplement can be approved from the standpoint of
`chemistry, microbiology, and drafi labeling.
`
`Dr. Advani noted that the following changes would have to be made for approval ofthe supplement:
`
`'1.
`
`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)”.
`
`.
`
`'2.
`
`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 ofEsmolol Hydrochloride'1n
`Sodium Chloride”.
`
`' Recommendation:
`
`An approval letter should issue for these supplements 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.
`
`Melissa Robb
`
`v5/28/03 04:28:45 PM
`CSO
`
`

`

`(: DEPARTMENTOFHEALTH&'HUMANSERVICES
`
`PublicHealthService
`
`. Food and Drug Administration
`Rockville, MD 20857
`
`NDA 19-386/S-022
`
`Baxter Healthcare Corporation, Anesthesia & Critical Care
`Attention: Ms. Priya Jambhekar
`Director, Regulatory Affairs
`- 95 SpringStreet
`New Providence, NJ 07974
`
`Dear Ms. Jambhekarz.
`
`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 hydrochloride in sodium chloride) Double Strength
`Injection, 20 mg/mL, in 5 mL ready to use glass vials
`
`NDA Number: 19-386
`
`Supplement number: 022
`
`Date of supplement: January 28,2003
`
`Date of receipt: January 30, 2003
`This supplemental application propose vial and carton labeling for the new DS product
`formulation, and also proposes revis