CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 017697-S012
`
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`
`
`KINEVAC
`
`Sincalide
`
`BRACCO
`
`11/27/2002
`
` stimulate gallbladder contraction, as may be assessed
`by various methods of diagnostic imaging, or to obtain
`by duodenal aspiration a sample of concentrated bile
`for analysis of cholesterol, bile salts, phospholipids,
`and crystals;
`
` 
`
` stimulate pancreatic secretion (especially in
`conjunction with secretin) prior to obtaining a duodenal
`aspirate for analysis of enzyme activity, composition,
`and cytology;
`
` accelerate the transit of a barium meal through the
`small bowel, thereby decreasing the time and extent of
`radiation associated with fluoroscopy and x-ray
`examination of the intestinal tract.
`
` 
`
`
`
`
`
`
`
`
`
`-1-
`
`
`
`
`MAIA Exhibit 1033
`MAIA V. BRACCO
`IPR PETITION
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 017697-S012
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`
`
`
`
`
`X
`X
`
`X
`
`X
`X
`
`
`X
`X
`
`-2-
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 017697-S012
`NDA 017697-8012
`
`APPLICATION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`-3-
`
`
`
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`
`
`
`
`Food and Drug Administration
`Rockville, MD 20857
`
`
`NDA 17-697/S-012, S-013, S-014, S-015
`
`Bracco Diagnostics
`Attention: Melanie Benson, M.S., R.A.C.
`Director, US Regulatory Affairs
`P.O. Box 5225
`Princeton, New Jersey 08543-5225
`
`Dear Ms. Benson:
`
`Please refer to your supplemental new drug applications dated August 28, 2002, received
`August 30, 2002, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`Kinevac® (sincalide) for Injection 5 mcg/vial.
`
`We acknowledge receipt of your submissions dated October 3, October 21, October 23, November 1,
`November 4, November 8, and November 20, 2002.
`
`These supplemental new drug applications provide for the following:
`
`1. Supplement-012 provides for the change in the manufacturing site for the drug product.
`
`2. Supplement-013 provides for the change in the formulation for the drug product.
`
`3. Supplement-014 provides for the change in the packaging for the drug product.
`
`4. Supplement-015 provides for the change in the testing for the drug product.
`
`We completed our review of these applications, as amended. These applications are approved,
`effective on the date of this letter, for use as recommended in the submitted labeling text.
`
`The final printed labeling (FPL) must be identical to the labeling package insert, vial label, and shipper
`label submitted August 28, October 3, and as amended on November 4, 2002.
`
`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
`10 of the copies on heavy-weight paper or similar material. For administrative purposes, these
`submissions should be designated "FPL for approved supplements NDA 17-697/S-012, S-013, S-014,
`S-015.” Approval of these submissions by FDA is not required before the labeling is used.
`
`We remind you of your postmarketing study commitments in your submissions dated
`November 8, 2002 and November 20, 2002.
`
`
`
`
`-4-
`
`
`
`
`

`

`NDA 17-697/S-012, S-013, S-014, S-015
`
`Page 2
`
`
`These commitments are listed below:
`1. To set specifications for impurities at the conclusion of the two-year stability study. The
`proposed specifications will be submitted as a prior approval supplement by March 2005.
`
`
`2. To test the three validation batches (initial timepoint) and the three stability batches
`(18-month timepoint) by both (b)(4)----------------- to provide comparative data. The results of
`these comparative studies will------------------------- in January 2003 as a prior approval supplement.
`
`
`3. To work with (b)(4)-------to reduce (or eliminate) the (b)(4)-----------------------------------------.
`The status and results will be reported in Annual Reports (July), with the final results being
`reported in the July 2004 Annual Report.
`
`
`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
`this division and two copies of both the promotional materials and the package insert directly to:
`
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`
`
`
`5600 Fishers Lane
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`
`
`
`
`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:
`
`
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`Although, not approvability issues, we have the following comment and recommendation.
`
`In the draft labeling, you have removed the periods after the N and J in N.J. to read as NJ except in the
`draft shipper label. For consistency, consider making this editorial change throughout the labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`-5-
`
`
`
`
`

`

`NDA 17-697/S-012, S-013, S-014, S-015
`
`Page 3
`
`
`
`
`If you have any questions, call Betsy Scroggs, Pharm. D., Consumer Safety Officer, at
`(301) 827-1250.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Robert L. Justice, M.D., M.S.
`Director
`Division of Gastrointestinal and Coagulation Drug Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-6-
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Robert Justice
`11/27/02 03:08:22 PM
`
`-7-
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 017697-S012
`NDA 017697-8012
`
`APPLICATION NUMBER:
`
`MEDICAL REVIEW(S)
`MEDICAL REVIEWg SQ
`
`
`
`
`
`-8-
`
`
`
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE
`
`TO:
`
`FROM:
`
`SUBJECT:
`
`October 31, 2002:
`
`Division File
`
`Hugo E. Gallo-Torres, MD, PhD, PNS
`Medical Team Leader (GI Drugs)
`Division of Gastrointestinal Drug Products
`HFD- 1 80
`
`NDA 17-697/SCM-012, Kinevac® for Injection
`Submission of August 28, 2002
`Sponsor: Bracco Diagnostics, Princeton, NJ
`
`Kinevac® (Sincalide for injection, USP) is a cholecystopancreatic-gastrointestinal hormone
`synthetically-prepared C-terminal octapeptide of cholecystokinin (CCK-8). CCK has many
`biological effects. It stimulates pancreatic enzyme secretion, causes gallbladder contraction,
`relaxes the sphincter of Oddi, enhances release/output of other hormones and has an effect on
`food intake.The precise indications for which the drug has been approved are 1) To stimulate
`gallbladder contraction; 2) To stimulate pancreatic secretion, and 3) To accelerate the transit of
`barium meal through the small bowel, thereby decreasing the time and extent of radiation
`associated with fluoroscopy and X—ray examination of the GI tractThe most important clinical
`use is as a diagnostic test for gallbladder contraction, for which, there are no drugs that can be
`used instead of CCK. Since its introduction in 1976 both manufacturing and analytical issues
`have been discussed between FDA and the sponsor at the time of the meeting or interaction.
`With the termination of contractual obligations with Bristol-Myers Squibb and the ensuing
`technology transfer of the product to a new manufacturing site, Ben Venue Laboratories, Inc.
`(Bedford, OH), Bracco (the current sponsor of the Kinevac NDA) used this 0
`ortuni
`to
`
`address various outstanding FDA issues. The standard method for&
`
`In essence, the current s nsor has reformulated the product, identified a new manufacturin site,
`Bracco seeks to eliminate the
`
`
`
`
`for the product .Because Kinevac® is currently on FDA’s Drug Shortages List and there is
`no alternative drug that can be used as a diagnostic tool for gallbladder contraction, this
`supplemental application is being assessed under Expedited Review. Reviews from the following
`disciplines are expected: Chemistry, Biopharmaceuticals, Pharmacolongoxicology ,
`Microbiology and Medical. In the present secondary review, reviews fiom each one of these
`
`-9-
`
`
`
`
`

`

`disciplines are considered. A recommendation for regulatory action is formulated on the basis of
`input fi'om this multidisciplinary approach
`
`1. CHEMISTRY.
`
`The reviewer, Dr. Marie Kowblansky, has concluded that the submission is approvable (with an
`18-month expiration for the product) pending resolution of the issues (1. through 8.) cited in the
`Draft Deficiency Letter , located on pages 9 and 10 of her review (date completed October 16,
`2002).
`
`2. MICROBIOLOGY
`
`The product Quality Microbiology Review, dated October 21, 2002 was carried out by Paul
`Stinavage. The application is recommended for approval on the basis of sterility assurance.
`The reviewer notes that Ben Venue Labs has upgraded its facility where the product is
`manufactured.
`4
`.,
`..
`4
`.
`p
`_
`p
`been properly installed or relocated. All ofthis is acceptable.
`
`«my
`Additionalitems have
`
`3. PHARMACOLOGY/TOXICOLOGY
`
`According to the reviewer, Dr. Sushanta Chakder, from a preclinical standpoint, the
`supplemental application is approvable Review date October 31, 2002). The reviewer notes a
`study comparing the gallbladder contractile effects of the 3 batches of Kinevac new formulation
`to the old formulation (control) after I.V. administration to guinea pigs. No differences in the
`gallbladder contractile effect were seen between different batches of the new vs the old
`formulation. In another acute toxicity study in mice , there was no difference 3 in the toxicology
`profiles between the new and old formulations . The reviewer notes further that to improve the
`stability of the new formulation, the sponsor has added several additional ingredients. In his
`opinion, the new ingredients, at the proposed concentrations, do not appear to pose any risk to the
`recipients. In conclusion, no apparent differences in the pharmacology and toxicology parameters
`were observed between the marketed, old formulation and the newly proposed formulation of
`Kinevac.
`
`4. BIOPHARMACEUTICS
`
`There is no Biopharm review available because a review is not needed. From interactions with
`Dr. Suresh Doddapaneni, Bioparm Team Leader, we conclude that, because the product is being
`administered intravenously, at the recommended dose and mode of administration as the old
`products, the product is 100% bioavailable . There are no scientific reasons to propose that the
`ingredients added to improve the stability of the drug in the new formulation might result in
`significant changes in the pharmacokinetic profile of the drug. Thus, from the Biophann
`viewpoint, the submission is approvable.
`
`5. MEDICAL
`
`There are neither efficacy nor safety concerns with the new formulation. The pharmacology data
`show no differences in gallbladder contractile effects between 3 batches of the new Kinevac
`formulation and the old, when these formulations are administered intravenously to guinea pigs.
`This is the standard bioassay to test CCK activity. The sponsor has adequately justified the
`
`-10-
`
`-10-
`
`
`
`
`

`

`choice of formulation components. Since they are all compendial, these formulation components
`are acceptable.
`
`
`
`a) They are part of the normal diet.
`b) They are administered parenterally (I.V.) as a usual component of TPN (Total Parenteral
`Nutrition) in patients that cannot ingest nutrients orally because of gut insufficiency. An
`
`exam 1e of TPN,
`
`c)
`
`In the newly proposed Kinevac® formulation are presents at concentrations (see above) that
`are far less than the
`
`
` (1) Each Sug Kinevac® vial contains
`on the calculations carried out by Dr.Chakder, the Pharm/Tox reviewer, these represent
`of the daily doses, respectively, being injected as TPN therapy.
`
`It is therefore concluded that the amounts of— present in the newly proposed
`Kinevac® formulation would not pose any safety risks to patients. In addition, Kinevac is used as
`a diagnostic test for one time only, although in practice, when the desired gallbladder contraction
`is not obtained with one injection, a second dose of the diagnostic test is administered. There is
`no reason to propose that 2 consecutive doses of the formulation would be of concern, from the
`safety viewpoint.
`
`RECOMNIENDATION FOR REGULATORY ACTION
`
`The new formulation of Kinevac, under supplement # SCM-012 to NBA 17-697 represents a
`significant im rovement over the old formulation. The new formulation is more stable, so that
`
`of the active ingredient sincalide in the currently approved formulation has been
`
`
`. The formulation is ex ected to perform as efiiciently as the old
`and the ingredients added such as‘ and other components do not
`
`
`represent a safety concern. Thus, the newly proposed Kinevac® formulation should be approved,
`pending resolution of the CMC deficiencies listed on pages 9 and 10 of Dr. M. Kowblansky’s
`review.
`
`-11-
`
`-11-
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`cc: HFD-180 File/RJustice/JKorvick/HGallo-Torres/
`cc: HFD- 1 80 File/RJustice/JKorvick/HGallo-Torres/
`LZhou/MKowblansky/JChoudary/SChakder/Pcooney/PStinavage/SDoddapaneni/BScroggs
`LZhou/MKowblansky/JChoudary/SChakder/Pcooney/P Stinavage/SDoddapaneni/BScroggs
`
`-12-
`
`-12-
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Hugo Gallo Torres
`11/1/02 07:21:54 AM
`MEDICAL OFFICER
`
`-13-
`
`
`
`
`

`

`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 017697-S012
`NDA 017697-8012
`
`APPLICATION NUMBER:
`
`CHEMISTRY REVIEW(S)
`CHEMISTRY REVIEWg S!
`
`
`-14-
`
`-14-
`
`
`
`
`

`

`
`1. Organization: HFD-180
`
`
`2. NDA Number: 17-697
`
`
`
`
` CHEMIST'S REVIEW #2
`
`
`
`3. Name and Address of Applicant (City & State):
`Bracco Diagnostics
`P.O. Box 5225
`Princeton, NJ
`
`
`6. Name of Drug:
`
`
`Kinevac® for injection
`
`
`7. Nonproprietary Name:
`
` sincalide
`
`
`8. Supplement Provides for:
`Change in formulation, manufacturing site and process, test
`methods
`
`
`
`
`
`
`
`
`4. AF Number:
`
` 5.Supplement(s)
`
`
`Numbers
`Dates
` SCM-012
`August 28, 2002
`SCF-013
`August 28, 2002
`SCP-014
`August 28, 2002
`SCS-015
`August 28, 2002
`
`9. Amendments and Other (Reports, etc.) Dates:
` SCM-012 BC November 8, 2002
`BC, C November 20, 2002
` SCF-013 BC November 8, 2002
`BC, C November 20, 2002
` SCP-014 BC November 8, 2002
`BC, C November 20, 2002
` SCS-015 BC November 8, 2002
`BC, C November 20, 2002
`
`
`12. Related IND/NDA/DMF(s):
`
`
`
`
`
`
`16. Records and Reports:
`
`Current
` Yes No
`
`Reviewed
` Yes No
`
`
`10. Pharmacological Category:
`
`gallbladder contraction stimulator
`for diagnostic testing
`
`
`13.Dosage Form:
` parenteral
`
`15. Chemical Name and Structure:
`cholecystokinin octapeptide
`Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2
`
`
`
`11. How Dispensed:
`
` RX F OTC
`
`
`
`
`14. Potency:
` 5 µg/vial
`
`
`
`
`
`
`
`
`
`
`
`17. Comments: See Review Notes
`
` cc: NDA 17-697
` HFD-180/Div File
` HFD-180/BScroggs
` HFD-180/MKowblansky
`HFD-180/ LZhou
`
`18. Conclusions and Recommendations: This supplement should be approved with the
`
`
`19. Reviewer
`
`
`
`Name: Marie Kowblansky, Ph.D.
`
`
`
`Signature:
`
`
`
`Date Completed: 11/20/02
`
`1 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`-15-
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Marie Kowblansky
`11/20/02 06:01:54 PM
`CHEMIST
`
`Liang Zhou
`11/21/02 01:14:37 PM
`CHEMIST
`
`-16-
`
`
`
`
`

`

`
`1. Organization: HFD-180
`
`
`2. NDA Number: 17-697
`
`
`
`
` CHEMIST'S REVIEW #2
`
`
`
`3. Name and Address of Applicant (City & State):
`Bracco Diagnostics
`P.O. Box 5225
`Princeton, NJ
`
`
`6. Name of Drug:
`
`
`Kinevac® for injection
`
`
`7. Nonproprietary Name:
`
` sincalide
`
`
`8. Supplement Provides for:
`Change in formulation, manufacturing site and process, test
`methods
`
`
`
`
`
`
`
`
`4. AF Number:
`
` 5.Supplement(s)
`
`
`Numbers
`Dates
` SCM-012
`August 28, 2002
`SCF-013
`August 28, 2002
`SCP-014
`August 28, 2002
`SCS-015
`August 28, 2002
`
`9. Amendments and Other (Reports, etc.) Dates:
` SCM-012 BC November 8, 2002
` SCF-013 BC November 8, 2002
` SCP-014 BC November 8, 2002
` SCS-015 BC November 8, 2002
`
`12. Related IND/NDA/DMF(s):
`
`
`
`
`
`
`16. Records and Reports:
`
`Current
` Yes No
`
`Reviewed
` Yes No
`
`
`10. Pharmacological Category:
`
`gallbladder contraction stimulator
`for diagnostic testing
`
`
`13.Dosage Form:
` parenteral
`
`15. Chemical Name and Structure:
`cholecystokinin octapeptide
`Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2
`
`
`
`11. How Dispensed:
`
` RX F OTC
`
`
`
`
`14. Potency:
` 5 µg/vial
`
`
`
`
`
`
`
`
`
`
`
`17. Comments: See Review Notes
`
` cc: NDA 17-697
` HFD-180/Div File
` HFD-180/BScroggs
` HFD-180/MKowblansky
`HFD-180/ LZhou
`
`18. Conclusions and Recommendations:
`
`This supplement is approvable (with an 18-month expiration for the product) pending resolution of the issue cited
`in the Draft Deficiency letter (at the end of the review).
`
`
`19. Reviewer
`
`
`
`Name: Marie Kowblansky, Ph.D.
`
`
`
`
`Date Completed: 11/15/02
`
`
`
`Signature:
`
`3 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`-17-
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Marie Kowblansky
`11/19/02 01:17:30 PM
`CHEMIST
`
`Liang Zhou
`11/19/02 01:44:16 PM
`CHEMIST
`
`-18-
`
`
`
`
`

`

`
`
`
` CHEMIST'S REVIEW #1
`
`
`
`1. Organization: HFD-180
`
`
`2. NDA Number: 17-697
`
`
`
`
`
`
`
`
`3. Name and Address of Applicant (City & State):
`Bracco Diagnostics
`P.O. Box 5225
`Princeton, NJ
`
`
`6. Name of Drug:
`
`
`Kinevac® for injection
`
`
`7. Nonproprietary Name:
`
` sincalide
`
`
`8. Supplement Provides for:
`Change in formulation, manufacturing site and process, test
`methods
`
`10. Pharmacological Category:
`
`gallbladder contraction stimulator
`for diagnostic testing
`
`
`13.Dosage Form:
` parenteral
`
`15. Chemical Name and Structure:
`cholecystokinin octapeptide
`Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2
`
`
`
`11. How Dispensed:
`
` RX F OTC
`
`
`
`
`14. Potency:
` 5 µg/vial
`
`
`
`
`
`
`
`
`
`
`
`17. Comments: See Review Notes
`
`
`4. AF Number:
`
` 5.Supplement(s)
`
`
`Numbers
`Dates
` SCM-012
`August 28, 2002
`SCF-013
`August 28, 2002
`SCP-014
`August 28, 2002
`SCS-015
`August 28, 2002
`
`9. Amendments and Other (Reports, etc.) Dates:
`
` October 21, 2002
`
`12. Related IND/NDA/DMF(s):
`
`
`
`
`
`
`16. Records and Reports:
`
`Current
` Yes No
`
`Reviewed
` Yes No
`
` cc: NDA 17-697/SCM012
` HFD-180/Div File
` HFD-180/BScroggs
` HFD-180/MKowblansky
`HFD-180/ LZhou
`
`18. Conclusions and Recommendations:
`
`This supplement is approvable (with an 18-month expiration for the product) pending resolution of the issues cited
`in the Draft Deficiency letter (located at the end of the review) and completion of the Medical, Pharm/Tox, and
`Biopharm reviews.
`
`
`19. Reviewer
`
`
`
`Name: Marie Kowblansky, Ph.D.
`
`
`
`
`Signature:
`
`
`
`Date Completed: 10/16/02
`
`
`
`9 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
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`-19-
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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/
`---------------------
`Marie Kowblansky
`10/28/02 01:06:31 PM
`CHEMIST
`
`Liang Zhou
`10/28/02 01:26:16 PM
`CHEMIST
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`
`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`
`
`
`
`APPLICATION NUMBER:
`NDA 017697-S012
`NDA 017697-8012
`
`APPLICATION NUMBER:
`
`PHARMACOLOGY REVIEW(S)
`PHARMACOLOGY REVIEW! S!
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`PHARMACOLOGIST’S REVIEW OF NDA 17-697
`(Supplement # SCM – 012 Dated August 28, 2002)
`
`
`
`Sponsor and Address: Bracco Diagnostics Inc.
`
`
`
` Princeton, NJ 08543
`Reviewer: Sushanta Chakder, Ph. D.
`
` Pharmacologist, HFD-180
`Date of Submission: August 28, 2002
`Date of HFD-180 Receipt: August 30, 2002
`Date of Review: October 31, 2002
`Drug: Kinevac (Sincalide) for Injection
`Category: Cholecystopancreatic-gastrointestinal hormone
`Proposed Marketing Indication: Diagnostic to stimulate gallbladder contraction and pancreatic
`secretion and/or intestinal mobility.
`
`Dose: Intravenous - 0.02 µg/kg to 0.12 µg/kg.
`Intramuscular- 0.1 µg/kg
`
`
`SUBMISSION CONTENTS:
`
`Kinevac (Sincalide) for Injection is currently approved in the US for its use (1) to stimulate gall bladder
`contraction, (2) to stimulate pancreatic secretion, and (3) to accelerate the transit of barium meal through
`the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-
`ray examination of the intestinal tract. The drug is on short supply because the manufacturer of the drug
`substance and product, BMSqiubb, stopped manufacturing Kinevac due to closure of their
`manufacturing facility. To improve the stability of the active drug, the sponsor, Bracco Diagnostics Inc.
`has reformulated Kinevac. The revised Kinevac formulation will be manufactured in Ben Venue
`Laboratories (BVL), Bedford, OH. The compositions of the old formulation and the new formulation
`are as follows:
`
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`(b) (4)
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`2
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` In the present supplemental application, the sponsor has submitted full reports of the following
`preclinical studies:
`1. Pharmacology study to evaluate the responsiveness of guinea pig gallbladder to Kinevac following
`intravenous injection,
`2. Acute toxicity study of Kinevac in mice by the intravenous route.
`
`
`PHARMACOLOGY:
`
`Evaluation of Guinea Pig’s Gallbladder Responsiveness in situ Following Intravenous Injection of
`Kinevac®. Comparison Between Batches 197559, 207146 and 243032 (Study # RF-01-0091).
`
`Methods: The study was conducted to compare the gallbladder contracting effects of the new
`formulation of Kinevac with that of the old formulation in a guinea pig model. Three batches of the new
`formulation were compared with a control batch of the old formulation in their ability to contract the
`gallbladder. Kinevac was administered intravenously at doses of 0.0078, 0.0156, 0.0312 and 0.0624
`µg/kg. The maximum tension developed after administration of a dose was measured in grams.
`
`Results: All three batches of the new Kinevac formulation (batch nos. 197559, 207146 and 243032)
`caused contractions of the guinea pig gall bladder in a dose-dependent manner. The control article
`(batch # OB28194) also produced similar contractions and no differences in the contraction were
`observed between different batches.
`
`
`The gallbladder tensions in grams after administration of different doses of the three batches of the new
`formulation and the control batch of Kinevac is summarized in the Table below.
`
`Table: Effect of different doses of Kinevac on guinea pig gall bladder (grams of tension; mean ± S.D)
`0.0078 µg/kg
`0.0156 µg/kg
`0.0312 µµg/kg
`0.0624 µg/kg
`Batch #
`0.67 ± 0.10
`1.05 ± 0.26
`1.45 ± 0.29
`2.17 ± 0.33
`197559
`0.67 ± 0.12
`1.03 ± 0.28
`1.52 ± 0.22
`2.22 ± 0.32
`207146
`0.62 ± 0.26
`1.08 ± 0.22
`1.57 ± 0.23
`2.33 ± 0.20
`243032
`0.63 ± 0.16
`1.05 ± 0.31
`1.38 ± 0.25
`2.22 ± 0.18
`OB28194 (Control)
`
`In summary, the gallbladder contractile effects of the three batches of Kenevac new formulation were
`compared with the old formulation (control) after IV administration in guinea pigs. No differences in
`the gallbladder contractile effect were observed between different batches of the new formulation and
`the old formulation.
`
`
`TOXICOLOGY:
`
`Study Title: Acute Toxicity of Kinevac after Intravenous Administration to Mice.
`
`Key study findings: In the single-dose IV acute toxicity study in mice, 1.0, 12.5 and 25 µg/kg doses of
`the new formulation and 25 µg/kg of the old formulation were administered to different groups of
`animals. There were no deaths of animals in any group. Treatment-related clinical signs, such as
`dypsnea and hypoactivity, were observed in animals receiving the 25 µg/kg dose of both formulations.
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`The clinical signs lasted for up to 30 minutes in animals receiving the new formulation, and for up to 4
`hours in animals receiving the old formulation. Thus, no difference in the toxicity profiles was observed
`between animals receiving the new and the old formulation.
`
`Study no: CdS149.
`
`Conducting Laboratory (and location if not sponsor): Bracco Imaging S.p.A, Via E. Folli,
`50 20134 Milan, Italy
`Dates of study initiation & completion: May 10, 2001 & October 04, 2001.
`
`GLP compliance: Yes
`
`QA Report Yes (X) No ( )
`
`Drug, Lot #, radiolabel (if applicable), and % purity: Kinevac new formulation, Batch no. 197559;
`Kinevac old formulation, Batch no. 57117021 (Control # OB28194).
`
`Formulation/vehicle: Lyophilized Kinevac (Sincalide) formulations were dissolved in sterile water for
`injection (1 µg/ml) before IV administration to the animals.
`
`Methods:
`Dosing:
`
`Species/strain: CRL : CD-1 (ICR) BR IGS mice.
`#/sex/group or time point: 12 animals/sex/group
`
`Age: Males- 9-weeks old, Females- 6 weeks old
`
`Weight: males – 26.0g – 30.2g, females – 22.5g – 26.1g.
`
`Doses in administered units: 1.0, 12.5 and 25 µg/kg doses of the new formulation, and the 25
`
`µg/kg dose of the old formulation was used.
`Route, form, volume, and infusion rate: The drug was administered via tail vein at a rate of 1
`
`ml/min (administration volume 5 ml/kg) using a Harvard infusion pump.
`
`Observations and times:
`
`Clinical signs: The animals were observed before dosing, immediately after dosing, and 5 min,
`
`30 min, 1, 2, 4 and 6 hours after dosing. During the observation period, the animals were observed twice
`a day.
`Body weights: Body weights were recorded on Days –3, 0 (dosing day), 2, 7 and 13.
`
`Hematology: Blood samples for hematological examinations were collected before sacrifice on
`
`Days 3 and 15 after dosing.
`Gross pathology: Half of the animals were sacrificed on Day 3 and the rest of the animals were
`
`sacrificed on Day 15 by cardiac puncture under anesthesia. All animals were subjected to macroscopic
`examination. The following organs were collected for histopathology examinations: kidney, liver, lungs,
`gall bladder and intestine.
`
`
`Results:
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`Mortality: There was no mortality in any group.
`
`Clinical signs:
`
`Animals receiving 1.0 and 12.5 µg/kg doses of the new formulation showed no clinical
`
`
`signs related to treatment with Kinevac. All males and 1 female (of 12) receiving the 25 µg/kg dose
`showed signs of dyspnea immediately after dosing, and hypoactivity was observed 5 minutes after
`dosing. The clinical signs disappeared within 30 minutes after dosing.
`Only one dose of the old formulation (25 µg/kg) was used in the study. All males and 4 females
`
`receiving the drug had dyspnea immediately after dosing and lasted for up to 1 hr after dosing.
`Hypoactivity was observed in all males and few females that lasted for 30 minutes to 4 hours.
`
`Body weights: No changes in the body weights were observed in any group.
`
`Hematology: No treatment-related changes in the hematological parameters were observed in
`
`any group.
`Gross pathology: No treatment related changes were observed in any group.
`Histopathology: Histopathological examinations of the kidneys, liver, lung, gall bladder and
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`intestine, conducted on Days 3 and 15, did not show any treatment-related changes in any group.
`
`
`In summary, in the acute toxicity study was conducted in mice with the new formulation of
`Kinevac after IV administration of 1.0, 12.5 and 25 µg/kg doses and compared with the 25 µg/kg dose
`of the old formulation. There were no deaths in any group; so the minimal lethal dose was not known.
`Treatment related clinical signs such as dyspnea and hypoactivity were observed in animals receiving
`the 25 µg/kg dose of both the old and the new formulation. The clinical signs were observed within 5
`minutes of dosing, and lasted for up to 30 minutes in animals receiving the new formulation and for up
`to 4 hours in animals receiving the old formulation of Kinevac. No treatment-related gross or
`histopathological changes were observed in any groups of mice sacrificed on Days 3 and 15. Thus, there
`were no differences in the toxicology profiles between the new and the old formulation in the acute
`toxicity study in mice. The earliest time at which the gross and histopathological examinations were
`conducted was 48 hours after dosing. Histopathological examinations were conducted only of limited
`tissues and no blood chemistry determinations were done in this acute toxicity study.
`
`
`
`SUMMARY AND CONCLUSION:
`
`
`Sincalide is a cholecystokinin C-terminal octapeptide and it evokes a variety of biological
`responses, including smooth muscle contraction of the gallbladder and small intestine, relaxation of the
`choledochoduodenal junction, protein secretion by the pancreas and acid secretion by the stomach. It is
`more potent than cholecystokinin on a weight or molar basis. Sincalide (Kinevac) for Injection is
`currently approved in the US as a diagnostic agent to stimulate gall bladder contraction, to stimulate
`pancreatic secretion, and to accelerate the transit of barium meal through the small bowel. The
`recommended doses for gall bladder contraction ranges from 0.02 to 0.12 µg/kg i.v., or 0.10 µg/kg i.m.
`For stimulation