CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`21-212
`
`CORRESPONDENCE
`
`_ y
`‘ g.
`
`

`

`t. ._ -
`
`JAN 272000
`
`NDA21-2l2
`
`Pharmacia & Upjohn
`Attention: Terry Reinstein
`Regulatory Manager
`7000 Portage Road
`Kalamazoo, MI49001
`
`Dear Mr. Reinstein:
`
`We have received your new drug application (NDA) submitted under section 505(b) of the Federal Food};
`Drug, and Cosmetic Act for the following:
`7 g5
`.3:-
`
`CaverjectDC (alprostadil for injection)
`
`Name ofDrug Product:
`
`—
`
`Therapeutic Classification: Standard (S)
`
`Date of Application:
`
`January 20, 2000
`
`Date of Receipt:
`
`January 21, 2000
`
`Our Reference Number:
`
`NDA 21~212
`
`Unless we notify you within 60 days of our receipt date that the application is not sufficiently complete to
`permit a substantive review, this application will be filed under section 505(b) of the Act on
`March 21, 2000, in accordance with 21 CFR 314.101(a). Ifthe application is filed, the primary user fee
`goal date will be November 21, 2000, and the secondary user fee goal date will be January 21, 2001.
`
`I Be advised that, a;of April 1, 1999, all applications for new active ingredients, new dosage forms, new
`indications, new routes ofadministration, and new dosing regimens are required to contain an assessment
`of the safety and effectiveness ofthe product in pediatric patients unless this requirement is waived or
`deferred (63 m.- [Lyon have not already fulfilled the requirements of 21 CFR 314.55 (or 601.27),
`please submit yolir plans for pediatric drug development within 120 days from the date ofthis letter unless
`you believe a waiver is appropriate. Within approximately 120 days of receipt of your pediatric drug
`development plan, we will review your plan and notify you of its adequacy.
`
`If you believe that this drug qualifies for a waiver of the pediatric study requirement, you should submit a
`request for a waiver with supporting information and documentation in accordance with the provisions of
`21 CFR 314.55 within 60 days from the date of this letter. We will make a determination whether to grant
`or deny a request for a waiver of pediatric studies during the review of the application. In no case,
`however, will the determination be made later than the date action is taken on the application. If a waiver is
`
`

`

`.17-.-
`
`NDA21-212- -J-
`
`Page2
`
`not granted, we will‘a'sk you‘to submit your pediatric drug development plans within 120 days from the
`date of denial of the Waiver.
`
`Pediatric studies conducted under the terms of section 505A of the Federal Food, Drug, and Cosmetic Act
`may result in additional marketing exclusivity for certain products (pediatric exclusivity). You should refer
`to the Guidancefor Industry on Qualifingfor Pediatric Exclusiviay (available on our web site at
`www.fda.gov/cderlflig‘c) for details. Ifyou wish to qualify for pediatric exclusivity you should submit
`a "Proposed Pediatric Study Request" (PPSR) in addition to your plans for pediatric drug development
`described above. We recommend that-you submit a Proposed Pediatric Study Request within 120 days
`fi'om the date of this letter. If you are unable to meet this time frame but are interested in pediatric
`exclusivity, please notify the division in writing. FDA generally will not accept studies submitted to an
`NDA before issuance of a Written Request as responsive to a Written Request. Sponsors should obtain a
`Written Request before submitting pediatric studios to an NDA. If you do not submit a PPSR or indicate
`that you are interested in pediatric exclusivity, we will review your pediatric drug development plan and
`notify you of its adequacy. Please note that satisfaction of the requirements in 21 CFR 314.55 alone may 3,
`not qualify you for pediatric exclusivity. FDA does not necessarily ask a sponsor to complete the same
`g
`scope ofstudies to qualify for pediatric exclusivity as it does to fulfill the requirements ofthe pediatric . a
`rule.
`._‘,_,
`
`'
`
`Please cite the NDA number listed above at the top of the first page of any communications concerning
`this application. All communications concerning this NDA should be addressed as follows:
`
`U.S. Postal/Courier/OvemigLIt Mail:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Reproductive and Urologic Drug Products, HFD-580
`Attention: Division Document Room 178-20
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`If you have any questions, call Kim Colangelo, Regulatory Project Manager, at (301) 827-4260.
`
`\"
`
`,1
`
`\
`
`ml 1;!
`
`Sincerely,
`
`(.
`
`v ‘
`
`. .
`.s?;~..:_,
`
`3 ,
`7
`
`Terri Rumble, B.S.N.
`Chief, Project Management Staff
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`

`

`NDA21-212-
`Page3
`
`‘49
`
`cc:
`
`‘
`
`-
`
`—
`
`Archival NDA 21-212-
`HFD-SW/Div. Fits
`
`HFD-S80/K.Colnngelo/I‘.Rumble
`
`DISTRICT OFFICE
`
`Dramd by: lune/January 24, 2000
`Inifialed by:
`*
`’
`final:
`filennme:
`
`ACKNOWLEDGEMENT (AC).
`
`'j’w-w»qt"
`
`

`

`.ypmw‘
`
`DEPARTMENT OF HEALTH 1 HUMAN SERVICES
`
`Public Health Service
`
`a
`
`g
`
`FoodandDrugAdministration
`Rockvillc MD 20857
`
`- ;;
`
`'
`.
`
`NDA 21—212
`
`,
`
`g7
`’
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`
`~
`
`INFORMATION REQUEST LETTER
`
`Pharmacia & Upjohn
`Attention: Terry Reinstein
`Regulatory Manager
`7000 Portage Road
`Kalamazoo, MI 49001
`
`Dear Mr. Reinstein:
`
`Please refer to your new drug application (NDA) submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act for Caverject (alprostadil for injection) Dual-Chamber Syringe.
`
`We also refer to your submission dated August 3 l, 2000.
`
`"tar-"'4'“t”
`
`We are reviewing the proposed labeling sections of your submissions and have the following
`comments and information requests. We need your prompt written response to continue our evaluation '
`of your NBA.
`
`1. Comments on the physician and patient package insert are attached. Recommended deletions are
`listed as striketlfleugh-text, and added text isW.
`
`2. Mock-up labels for the container and cartons should be submitted.
`
`3. The statement “Keep out of reach of children” should be added to the carton label.
`
`4. References to the originally proposed trademark Caverject “DC” have been removed. These
`sections can be replaced once a trademark for this product has been determined.
`
`If you have any questions, call Kim Colangelo, Regulatory Project Manager, at (301) 8274260.
`
`Sincerely,
`
`Terri Rumble
`
`Chief, Project Management Staff
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation 111
`Center for Drug Evaluation and Research
`
`ATTACHMENT
`
`

`

`ipages redacted from this section of
`the approval package consisted of draft labeling
`
`O
`
`
`
`
`
`’Lfl'"w-q"I‘‘
`
`

`

`pages redacted from this section of
`3!
`the approval package consisted of draft labeling
`
`O
`
`
`
`I't‘www-mQt”
`
`

`

`__’2}___pages redacted from this seCtion of
`the approval package consisted of draft labeling
`
`O
`
`,iww
`
`

`

`
`

`

`_, -- ' ,
`
`‘ DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NEEMORANDUM
`
`Public Health Service
`
`-
`
`_
`
`_
`1"" a .
`
`_
`
`-
`
`'
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`DATE:
`
`October 4, 2000
`
`FROM:
`
`Karen Lechter, HFD-42
`
`TO:
`
`Barbara Chong, HFD-42
`
`SUBJECT: Caverject DC PPI
`NDA 21-212
`
`Attached are two copies of the proposed PPI for Caverject DC. One tracks the changes _
`we propose from the sponsor’s original. The other is a clean copy.
`
`We propose the following changes:
`Insert an introductory paragraph
`
`Simplify wording
`Use headings we propose for most new PPI’s
`Group similar information
`
`_
`
`'
`
`‘L-I'muw.‘1’
`
`I embedded the questions in the text in brackets and italics.
`I had a number of questions.
`They deal with issues such as whether certain information should be included and how to
`clarify some information.
`
`In addition to these questions, the review division should consider whether to add a
`warning about the possibility of needle breakage, how to avoid it, and what to do if it
`occurs. The division should also consider whether to warn against using other impotence
`medications at the same time.
`
`a
`
`CC:
`
`HFDAWsuigve/I‘abak/Reading
`NDA 21-212
`
`KLechter 10/4/00
`NON-RELEASABLE
`
`

`

`-
`Caverject Deflfibeting‘comments
`NDA 21-212
`.
`‘
`
`Pharmaéokingic'tinSpecial Populations
`
`Pediatric
`
`19mm Embomflbrg
`DDMAQ
`
`Is this section necessary? It could be used as an off-label use for Caverject DC.
`
`Clinical Studies
`
`Study 1:
`
`“In the double-blind phase, each dose of Caveiject was significantly more effective than
`placebo by clinical evaluation (“full penile rigidity”) and by RigiScan criteria (70%
`rigidity for at least 10 minutes); there was no response to placebo”
`Would it be possible to quantify the results by adding the percentage of patients in each
`group that achieved full penile rigidity by clinical evaluation and RigiScan criteria?
`
`in
`
`
`~———~_—
`” How is “:
`\.—’——— ‘defined? would itbe ,
`
`W 7” In study 3,
`
`,,
`
`the same wording is used (
`
`-——\___—————/\
`
`
`
`L'N‘a‘ewq"‘
`
`Study 2:
`“The differences in the response rates in both, the clinical and the RigiScan evaluations
`between each of the doses of Caverject and placebo were statistically significant.”
`
`W
`
`Next paragraph afier Study 3:
`
`-
`""7: 7 _7
`‘
`between the twp formulations?
`
`‘
`
`Systemic AWEvients
`1
`
`,
`
`" Is that the only difference
`
`“However, these changes were usually clinically unimportant; only three patients
`discontinued treatment because of symptomatic hypotension.” Could we delete the first
`part of the sentence (However, these changes were usually clinically unimportant) and
`the word “only”?
`
`

`

`A pages redacted from this section of
`the approval package consisted of draft labeling
`
`O
`
`
`
`‘'LM‘W»4"
`
`

`

`pages redacted from this section of
`El
`the approval package consisted of draft labeling
`
`0
`
`Ila-WW
`
`

`

`CAVERJECT DC (NDA 21-212) Dual Chamber Syringe
`Pharmacia & Upjohn Company
`
`Item 3: Summary
`Vol.
`1 / Pg. 79
`
`3.3 FOREIQIfi MARKETING HISTORY
`n‘
`
`3.3.1 List-of Countries where Marketed and Dates of Approval
`
`3.3.1.1 CAVERJECT Dual Chamber
`
`CAVERJECI‘ DC (alprostadil for injection) is not currently marketed anywhere in the world.
`
`The ‘
`
`
`3.3.1.2 CAVERJECT Sterile Powder
`
`CAVERJECT® Sterile Powder (alprostadil for injection; available in vials of 5, 10, 20, and
`40 ug) was approved on 5 July 1995 for the treatment and diagnosis of ED (NDA 20-379).
`As of 7 December 1999, CAVERJECT® Sterile Powder had been approved in 71 countries
`worldwide (Table 3.3—1).
`
`Table 3.3-1. Worldwide Registrations ot CAVERJECT Sterile Powder
`Al roetedil for In
`
`
`
`3
`’ é
`‘
`fir
`"v
`
`.’
`
`-
`
`l (4)
`
`

`

`Item 3: Summary
`CAVERJECT DC (NDA 21-212) Dual Chamber Syringe
`
`
`Vol.Pharmacia & Upjohn Company 1 / Pg. 80
`
`_
`.«.-
`
`,,
`
`
`
`
`Table 3.3-1. Worldwide Registrations of CAVERJECT Sterile Powder
`-
`Al - rostadii for In action
`
`
`
`WIT-M'-
`
`
`
`
`
`
`
`
`
`
`
`November1995
`
`November1996
`
`Rn blic
`
`Greece
`
`
`
`
`December1994 E'fl_ November1994
` W March 1995
`W Febma
`1995
`
`October1994
`
`W 1995 W M
`TOI : e I
`
`
`
`M
`
`
`
`3.3.1.3 CAVERJECT Injection
`
`CAVERJECT® Injection [(aiprostadil injection) aqueous; available in amounts of 10, 20, and
`40 pg) was approved on 31 October 1997 for the treatment and diagnosis of ED
`(NDA 20-755). As of 7 December 1999, CAVERJECI‘ Injection had been approved in ll
`countries worldwide (Table 3.3—2).
`
`Table 3.3-2. Worldwide Registration: of ‘
`CAVEBJECT Injection
`
` United States
`
`__
`
`Venezuela
`
`

`

`CAVERJECT DC (NDA 21-212) Dual Chamber Syringe
`Pharmacia & Upjohn Company
`1Vol. /Pg.81
`
`
`
`
`
`Item 3: Su
`
`_g}—
`
`3.3.1.4
`
`PROSTIN VR Pediatric Sterile Solution
`
`PROSTIN VR Pediatric® Sterile Solution (alprostadil injection, USP; available at a
`conceritratiogoféOO-ug/mi.) was approved on 16 October 1981 for use as palliative therapy
`to temporarily‘hlaintain the patency of the ductus arteriosus in neonates with congenital heart
`defects (NDA 18-484). Alprostadil sterile solution is registered for this indication in
`54 countries (Table 3.3-3) and is marketed outside the United States under the following trade
`names: PROSTINTM VR, MINPROG'" PAED, PROSTIVAS'", PROLESINATM VR, and
`PROSTINETM VR.
`
`Table 3.3-3. Worldwide Registrations ot PROSTIN VR Pediatric Sterile
`
` Ea
`it?1.Iiliiil §§§
`18%ll r?
`32gE:aagr§§ Ma 1987
`9.$31139
`Iiigiii
`
`
`
`
`1mm.
`
`'Iand
`unasaa
`
`
`
`
`July 1987
`
`United Arab
`Emirates
`
`ll
`
`
`
`3 (4)
`
`lam-w»qr”
`
`June 1994
`June 1983
`Jul 1997
`Janu-
`1985
`March 1982
`
`August1992
`
`November 1989
`March 1985
`March 1988
`March 1992
`
`Jena
`1993
`Jul 1989
`June 1983
`
`‘
`
`:- ember1995
`Februa
`1983
`Ma 1983
`June 1986
`Jan :
`1983
`Feb :
`1989
`:
`1992
`53:? §
`October 1993
`
`8‘:5%
`
`981
`
`
`
`
`
`E
`
`:3;
`
`i
`
`§
`
`: . ember 1986
`--tember 1986
`
`.3
`
`0:08A—
`
`ovakia (Slovak
`
`ovenia
`Africa
`
`1984
`ber1985
`
`:
`
`?i§§5fasa
`
`June 1993
`
`% r
`
`t g?
`
` D
`9'“o9
`
`Czech Republic
`
`rk
`Finland
`
`German
`
`

`

`Item 3: Summary
`CAVERJECT DC (NDA 21-212) Dual Chamber Syn'nge
`
`
`Vol.Phannacia & Upjohn Company 1 / Pg. 82
`
`a-.-
`
`3.3.2 List of Countries where Approvals Are Pending and Dates of
`Applicatiggg,
`
`3.3.3 Information from Regulatory Bodies Refusing Drug Approval on
`Grounds of Safety
`
`To date, no regulatory agency has withdrawn or rejected CAVERJECT for safety reasons.
`
`
`
`Lw‘l‘wlwW”‘I v 0
`
`4
`
`4 (4)
`
`

`

`1*:
`
`_
`
`-
`
`-
`
`SEP 192000
`
`DISCIPLINE REVIEW LETTER
`
`‘
`
`\t
`
`NDA 21-212
`
`Pharmacia & Upjohn
`Attention: Terry Reinstein
`Regulatory Manager
`7000 Portage Road
`Kalamazoo, MI 49001
`
`Dear Mr. Reinstein:
`
`Please refer to your new drug application (NDA) submitted under section 505(b) ofthe Federal Food,
`Drug, and Cosmetic Act for Caverject (alprostadil for injection) Dual-Chamber Syringe.
`
`' 3
`‘
`3.
`.L
`
`We also refer to your submission dated May 31, 2000.
`
`Our review of the Chemistry section of your submission is complete, and we have identified the following
`deficiencies:
`
`l. Deficiencies have been noted for
`holder.
`
`
`
`; and will be separately addressed with the DMF
`
`2.
`
`Information is needed on the packaging and storage conditions used during shipment of the drug
`substance.
`
`3. Certificates of Analysis (COAs) for the batches of drug substance used in manufacturing the drug
`product are needed.
`
`4. Primary stability-data for six batches to 6-months at 40°C/7S°/o RH show that during a six month
`period, the perant water increases from an initial value of — to — V. This accelerated data can be
`used to estimate thatat—ZS"C by about 18 months, the amount of water present will be approximately
`"" Therefdl‘ve'fihespecification for the amount of water to be v— at time of release is not sufficient to
`allow for any’ water increase that will occur during the expiration period. The specification for water
`, needs to be revisedto include a release specification of not more than (NMT) .- Yo and a through
`shelf-life specification of NMT -
`
`S. A detailed procedure for the measurement of volume of injection needs to be provided.
`
`6. A sampling procedure for the analysis of the drug product needs to be provided.
`
`7. The sterility of the wiping tissues to be used with the drug product needs to be established.
`
`

`

`NDA21-212
`
`Page2
`
`-_~ "
`
`8. The proposed expiration date of ”,— is not acceptable A ——-—-—— expiration date can be
`granted base¢9nthe 6-months real-time and 6-months accelerated data submitted for the primary
`stability Batches.A
`-
`,
`.
`
`9. The Stability Commitment needs to be revised to state that the expiration date will be extended based
`on full real-time stability data from the first three commercial lots.
`
`10. Table C provided in your Stability Commitment indicates that the 6- and 18-month test intervals will
`not be carried out if the shelf-life exceeds two years. All time intervals should be carried out for any
`batches in stability. The Stability Commitment needs to be revised accordingly.
`
`11. A new proprietary name for this product should be submitted.
`
`.
`
`We are providing these comments to you before we complete our review of the entire application to give
`you prelimingy notice of issues that we have identified. In conformance with the prescription drug user
`fee reauthorization agreements, these comments do not reflect a final decision on the information reviewed
`and should not be censtrued to do so. These comments are preliminary and subject to change as we _;
`finalize our review of your application. In addition, we may identify other information that must be
`5
`provided before we can approve this application. If you respond to theseIssues during this review cycIi
`depending on the timing of your response, and1n conformance with the user fee reauthorization
`—
`agreements, we may not be able to consider your response before we take an action on your application
`during this review cycle.
`
`If you have any questions, call Kim Colangelo, Regulatory Project Manager, at (301) 827-4260.
`
`Sincerely,
`/
`'
`‘
`
`'
`
`/
`
`65W.“
`
`r1)
`
`Moo-Jhong Rhee, PhD.
`Chemistry Team Leader for the
`Division of Reproductive and
`Urologic Drug Products, (HFD-580)
`DNDC II, Office of New Drug Chemistry
`Center for Drug Evaluation and Research
`
`7 ,
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`

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`NDA 21-212 :° ‘
`Page 3
`
`cc:
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`P...—_ :4
`L '2‘"
`.
`
`Archival NDA 21—2'1-2
`I-{FD-580/Div. Files;
`
`HFD-580/K.Colangelo
`HFD-S80M.Rhee/J.Salemme
`HFD-820/1.Gibbs
`DISTRICT OFFICE
`
`Drafied by: kmc/September 13, 2000
`Initialed by: Rumble, 09.13.00; Salemme, 09.14.00; Rhee, 09.15.00; Allen, 09.18.00
`final: Colangelo, 09.18.00
`filename: c:\data\nda\2 l -212\drcmc.doc
`
`DISCIPLINE REVIEW LETTER (DR)
`
`'Lh“'w"Qt”
`
`

`

`
`
`x»._§uir.+
`
`_
`
`‘1‘.
`l
`
`

`

`J2”! I
`
`DISCIPLINE REVIEW LETTER
`
`AUG 2 5 2000
`
`NDA 21-212
`
`_’—L»'——
`--~.-
`
`Pharmacia & Upjohn-1
`Attention: Terry Reinstein
`Regulatory Manager
`7000 Portage Road
`Kalamazoo, MI 49001
`
`Dear Mr. Reinstein:
`
`Please refer to your new drug application (NDA) strbmitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act for Caveiject DC (alprostadil for injection).
`
`We also refer to your submission dated June [5, 2000.
`
`-
`
`-
`
`at
`
`Our review of the Microbiology section of your submission is complete, and we have identified the
`following deficiencies:
`
`I.
`
`It appears that following filling of fi'ont cartridge chamberthe cartn'dges must pass through the
`’— ‘area prior to being loaded into the freeze-dryer. Following the freeze-dry cycle the open
`
`cartridges must again pass through a
`prior to capping of the front chamber and
`filling of the rear chamber. It is not clear what steps are taken to protect the filled, but uncapped,
`cartridges from microbiological contamination during transit to and from the freeze-dryer. The
`methods used to protect the open cartridges should be provided. These methods should include
`protocols and results from any validation experiments for equipment used to accomplish this.
`
`3'
`'5
`'
`.E:
`._ ~
`
`2. Only one equipment load pattern is described for sterilization in : Ms,“
`_,-—-——------
`It should be clarified whether this is the only load to be sterilized using
`this equipment. If not, validation data for each load sterilized using this equipment should be
`specified and validation data provided for each load processed using this equipment.
`
`We are providing these comments to you before we complete our review of the entire application to give
`you pre_limi_ng1.nnti¢e_pf issues that we have identified. In conformance with the prescription drug user
`fee reauthorizationjagreements, these comments do not reflect a final decision on the information
`reviewed and should not be-construed to do so. These comments are preliminary and subject to change as
`we finalize our review of your application.
`In addition, we may identify other information that must be
`provided before fiemréppmve this application. If you respond to this issue during this review cycle,
`depending on the‘timing of your response, and in conformance with the user fee reauthorization
`agreements, we may not be able to consider your response before we take an action on your application
`during this review cycle.
`
`

`

`NDA 21.212
`Pagez
`
`.
`
`H
`
`r_ ,_ 7'
`
`‘
`
`If you have any questions, call Kim Colangelo, Regulatory Project Manager, at (301) 827-4260.
`-~- V
`
`Sincerely,
`
`Iberia
`
`Moo-Jhong Rhee, PhD.
`Chemistry Team Leader for the
`Division of Reproductive and
`Urologic Drug Products, (HFD-580)
`DNDC II, Office of New Dmg Chemistry
`Center for Drug Evaluation and Research
`
`”Lam-w»W”
`
`

`

`.‘-. _
`
`NDA21-212 -
`
`1..—
`
`Page 3
`
`£7.
`,
`'
`cc:
`Archival NDA 21-212 ' 4.
`HFD-580/Div. Fiieé f
`HFD-S 80/K.ColangeloM.Rhee/J.Salemme
`HFD-SOS/PCooney/RStinavage
`HFD-820/J.Gibbs
`DISTRICT OFFICE
`
`Draficd by: kmc/August 22, 2000
`Initialed by: Stinavage, Cooney, 08.24.00; Rhee, 08.25.00
`final: Colangelo, 08.25.00
`filename: c:\data\nda\2 l-212\drmicro.doc
`
`DISCIPLINE REVIEW LETTER (DR)
`
`Lva-w‘4"
`
`

`

`DUPLICATE
`
`Pharmacia8¢Upjohn
`
`.
`
`NDA O'RIG AMENDMENT
`
`May 24, 2002 _,_.:_
`-~- ,
`'
`‘
`‘
`Division of Reproductive and Urologic Drug Products HFD-58O
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`
`Attention: Division Document Room
`
`5 1’
`
`'
`
`'
`
`M
`
`Pharmacia & Upjohn
`7000 Portage Road
`
`gingé~(:;::;j;:
`
`RECEIVED
`
`MAY 2 8 2002
`
`"FD-WCDER
`
`Rockville, MD 20857
`
`Dear Sir or Madam:
`
`Re:
`
`NDA 21-212
`
`CAVERJECT® Dual Chamber Syringe
`(alprostadil for injection)
`
`Aiming-t
`Revised Insert Labeling
`
`Please refer to Pharmacia & Upjohn (P&U) correspondence dated December 10, 2001 for the
`NDA referenced above and the telephone contact of May 16, 2002 between FDA (Eufrecina
`Deguia) and P&U (Terry Reinstein). The purpose of this amendment is to provide a revised
`package insert with modified patient instructions, in accordance with Dr. Hirsch’s request (as per
`the telephone contact) that the word “usually" be removed from line 649 in the
`underline/Strikeout version of the Patient Instructions.
`
`zit-we
`
`We agree with Dr. Hirsch’s request; therefore, please refer to the attachments provided with this
`correspondence for revised insert labeling. The proposed insert is provided in two formats.
`Attachment 1 is presented in underline/Strikeout showing the changes versus FDA’s text per the
`approvable letter dated November 20, 2000 (including P&U’s comments/rationale for the
`proposed text), plus the change on line 649 in the patient instructions. Attachment 2 provides
`for a clean copy of the aforementioned underline/strikeout version; line 580 in this attachment
`corresponds to the change on line 649 of Attachment 1. Also, please note “Caverject * *” is used
`throughout the proposed insert wherever the final tradename for the product will appear, once
`approved.
`
`If you have any't-fr‘estfons regarding the information provided, please contact me at (616) 833-
`8542, or by fax at $16) 833-8237.
`‘
`
`Sincerely,
`
`.4
`
`if,» w.' t
`t
`
`PH
`
`ACIA & UP OHN COMPANY
`
`cage" 79% ”7317’ flee/"3km
`
`Terry . Reinstein, R. P .
`Regulatory Manager
`
`Desk Copy: Eufrecina Deguia , CSO/Division of Reproductive and Urologic Drug Products
`(HFD-SSO)
`
`

`

`:DUPUCAIE‘
`' Pharmacia&Upjohn
`sammm
`
`Pharmacia & Upjohn
`7000 Portage Road
`
`Telephone: (616) 8334000
`
`May 6, 2005. '
`
`'.
`
`Division of Reproductive & Urological Drug Products RFD-580
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Document Control Room l7B-3O
`5600 Fisher Lane
`Rockville, MD 20857
`
`Re:
`
`RECEIVED
`MAY
`
`0 8 2002
`H _
`FD 580/CDER
`0
`.
`I;
`NDA ORlG AMENDMENT
`NBA 21-212
`CAVERJECT® Dual Chamber Syringe
`(alprostadil for injection)
`
`Dear Sir or Madam:
`
`Amendment No. 016
`Response to FDA Request for CMC
`Information — Updated Stability Data
`
`-
`
`X,
`i
`5'
`__;t
`
`We are amending our NDA 21-212 for Caverject Dual Chamber Syringe in response to a
`request from FDA Consumer Safety Officer, Ms. Eufrecina Deguia, on March 18, 2002.
`Ms. Deguia asked that Pharmacia submit 36-month stability data for the product as soon
`as the data were available. In order to provide complete data for both the 10 mcg and 20
`mcg strengths of the product for review by FDA prior to the action date for this
`application of June 12, 2002, Pharmacia agreed to respond by the middle of May.
`
`The attached stability report contains data through 36 months in support of our request
`for 36—month expiration dating for both strengths of the product.
`
`Please contact Terry Reinstein at (616) 833-8542, if there are questions. Send all
`correspondence addressed to Unit 0633-2984 13.
`
`Sincerely,
`
`'
`
`PHARMAC‘ERE‘UHOW COMPANY
`
`, R.Ph.
`Terry L. Remstei
`Regulatory Manager
`Regulatory Affairs
`
`TLR:SEH
`
`Attachments
`
`

`

`'
`
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`
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`
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`33332121233322"
`
`D‘lD IVW‘l l" M
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`ORIGIr"L
`@ PharmaCIa&UpJohn o. 0,1U’9r‘
`
`Telephone: (616) 2333-4000
`
`December 10;th
`
`Division of Reproductive and Urologic Drug Products HFD-580
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Attention: Division Document Room
`5600 Fishers Lane
`
`ORIG AMENDMENT
`5 E
`
`Rockville, MD 20857
`
`
`
`RE: NDA 21-212
`
`CAVERJECT Dual-Chamber Syringe
`(Alprostadil for injection)
`
`Amendment
`Complete Response to Approvable Letter
`
`“
`
`t"
`u;
`*
`‘ ~3-
`
`Dear Sir or Madam:
`
`Please refer to the FDA correspondence dated November 20, 2000, in which you provided an
`approvable response for NDA 21—212. In addition, your correspondence identified deficiencies that
`remain pending, which must be addressed by Pharmacia & Upjohn (P&U) before this NDA may be
`approved. Therefore, the purpose of this correspondence is to amend NDA 21-212 in order to
`provide a complete response to the deficiencies noted in the approvable letter.
`
`P&U’s responses to the items listed in your November 20, 2000 letter are provided below. For ease
`of review, pending deficiencies identified in the approvable letter are shown in bold text, followed by
`our response.
`
`Item no. 1:
`
`_
`
`Until actual data are provided to demonstrate that the water content will not significantly
`affect the drugpfifduct during the shelf-life, specifications for water content need to be
`implemented as follOws: NMT "‘ at release and NMT ‘ 7o during shelf-life.
`
`*
`.—
`P&U Resmnse:
`A response t6‘fhii aéficiency was previously submitted to NDA 21-212 on November 17, 2000 as
`amendment no. 14 (see Attachment 1). For your convenience, the following is a reiteration of that
`response:
`‘
`
`We agree to accept the time of release and shelf-life limits cited by the reviewer, NMT J) and NMT
`- " Z2, respectively. Since multiple replicates are routinely run for this test, the limits will be applied
`to the average result.
`
`

`

`NDA 21-212
`CAVERJECT Dual-Chamber Syringe
`(Alprostadil for injection)
`Page 2
`
`g -
`,.-_— .
`Item no. 2: '
`Provide a bric'FOve’rall description of the sampling plan(s) for production batches and selection
`of the sub-samples for analysis. Evaluation should consider the adequacy of the sampling
`process (e.g. beginning, middle, end) and the number of samples per production batch.
`
`P&U Resggnéef, ’2
`A response to this deficiency was previously submitted to NDA 21-212 on November 17, 2000 as
`amendment no. 14 (see Attachment 1).
`
`Item no. 3:
`
`Based on 12 months of stability data at 25 C and 6 months at 40 C, an
`period can be granted.
`
`-—-,
`
`expiration
`
`P&U Resp_onse:
`P&U previously acknowledged this notification in our response submitted to NDA 21-212 on
`November 17, 2000 as amendment no. 14. However since that time, additional stability data are now
`available to support a 36-month expiration period for each strength of CAVERJECI‘ Dual Chamber
`Syringe (see Attachment 2), also known as CAVERJECT IMPULSE (see page 3 of this
`correspondence for additional information concerning this tradename).
`
`Item no. 4:
`
`.
`
`In addition, it will be necessary for you to submit revised draft labeling for the drug. The
`labeling should be identical in content to the attached labeling (text for the package insert
`text for the patient package insert). Carton labels must be revised to include the statement“
`“Keep out of reach of children.”
`
`-
`
`
`
`win-w.‘1“
`
`P&U Response:
`Please refer to Attachment 3 of this correspondence for revised insert labeling. The proposed insert
`is provided in two formats; one is in underline/Strikeout showing the changes versus FDA’s text per
`the approvable letter dated November 20, 2000, which also includes P&U’s comments/rationale for
`the proposed changes. The second format provides for a “clean” copy of the aforementioned
`underline/Strikeout version. Also, please note “Caverject **" is used throughout the proposed insert
`wherever the final tradename for the drug product will appear. once approved.
`
`Please refer to Attachment 4 of this correspondence for the manuscript version of the revised carton
`labeling, which includes the statement “Keep out of reach of children."
`——‘-.';._~"
`_
`as "3
`
`Item no. 5:
`
`During recent Espections of the manufacturing facilities for your NDA, a number of
`deficiencies were noted and conveyed to you or your suppliers by the inspector. Satisfactory
`inspections film-required before this application may be approved.
`
`P&U Response:
`The deficiencies noted during the June/July 2000 FDA inspections of our manufacturing facility have
`been addressed. We are prepared for a reinspection.
`
`REVEWS COMPLETED
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`,- DATE
`
`

`

`NDA 21-212
`CAVERJECI' Dual-Chamber Syringe
`(Alprostadil for injection)
`Page 3
`
`_
`Item no. 6:
`Under 21 CER-314.50(d)(5)(vi)(b), we request that you update your NDA by submitting all
`safety information you nowhave regarding your new drug. Please provide updated
`information as listed below. The update should cover all studies and uses of the drug
`including: (1)}th involving indications not being sought'In the present submission, (2) other
`dosage forms, and (‘3) other dose levels, etc.
`
`1. Details of any significant changes or findings.
`
`2. Summary of worldwide experience on the safety of this drug.
`
`3. English translations of any approved foreign labeling not previously submitted.
`
`4.
`
`Information suggesting a substantial difference in the rate of occurrence of common,
`but less serious, adverse events.
`
`P&U Response:
`Please refer to Attachment 5 of this correspondence, which contains the NDA Safety Update as
`requested in points no. 1, 2, and 4 above.
`
`Regarding point no. 3, please refer to Attachment 6 for the English translations for all approved
`foreign labeling of this drug product (Europe and Brazil).
`
`7EM“..-w,.*1“
`
`Tradename:
`
`Please refer to our correspondence dated November 21, 2001 submitted to IND 38,269 (serial no.
`122), in which we appeal for the use of CAVERJECT IMPULSETM as the proprietary name for the
`product. We would appreciate FDA's consideration of this appeal at the earliest possible
`opportunity.
`
`If you have any questions regarding the contents of this submission, please contact me at (616) 833-
`8542 or Dan Chirby at (616) 833-9411, or by fax at (616) 833-8237.
`
`Sincerely,
`
`P
`
`_
`
`CIA&'U?JOHN COMPANY
`
`i2- fi7/ Q ,. rifle
`Te
`.Reinstein, R Ph.
`Regulatory wager»—
`
`Desk Copy: Domette Spell-LeSane, CSO/Division of Reproductive and Urologic Drug Products
`(HFD-580)
`
`

`

`,
`
`. Pharmacia & Upjohn
`
`: (“r-'3‘
`
`7000 Portage Road
`Kalamazoo, MI 49001-0199
`
`Telephone: (616) 833-4000
`
`06W “ ‘
`
`DUPLICATE
`
`Division of Reproductive & Urological Drug Products HE)-580
`
`Center for Drug Evaluation and Research
`
`Food and Drug Administration
`Document Control Room l7B-30
`5600 Fisher Lane
`Rockville, MD 20857
`
`0' fl “END‘ENT
`B C
`
`Re:
`
`NBA 21-212
`
`CAVERJECT® DC
`
`alprostadil for injection
`
`Amendment No. 013
`Response to FDA Request for
`CMC Information - Chemistry
`
`‘3,
`i
`2
`.2:
`’— "
`
`,
`Dear Sir or Madam:
`
`We are amending our NDA 21-212 for Caveiject DC to provide responses to items 6 and 7
`in FDA’s discipline review letter of September 19, 2000. Our initial response to deficiencies noted
`in the September 19 letter was submitted in our Amendment No. 012 dated October 2, 2000.
`
`For ease of review, each original question is shown in italics, followed by our response. Tables,
`figures and attachments are numbered to be consistent with the question with which they are
`associated.
`
`Question 6
`A sampling procedure for the analysis of the drug product needs to be provided.
`
`,
`,
`Resmnse ,
`The samplinfixoeedure for the drug product is included as Attachment 6.
`
`.
`'
`Question 7
`The sterilitygig/1e? wiping tissues to be used with the drug product needs to be established.
`. i 4‘
`
`Response
`The wiping tissues are not claimed to be sterile. The tissues are described in Part 2.F.5.c
`of Item 4A of the NDA.
`
`As discussed with Ms. Kim Colangelo. FDA Project Manager, we are awaiting clarification from the
`FDA of the deficiencies noted in item 1 of your September l9 letter. Note that Pharmacia & Upjohn
`(P&U) provided responses to questions concerning the drug substanc‘
`in our
`Amendment No. 002 dated May 31, 2000. Additionally, as conveyed to Ms. Colangelo, we are
`actively engaged in a selection process for a new proprietary name (item 1 l) and will submit this
`information to the agency as soon as it becomes available.
`v
`
`

`

`NDA 21-212
`
`Page 2
`
`Please contactl‘erry fieinstein at (616) 833-8542, if there are questions. Send all correspondence
`addressed thnit 0633—298-113.
`
`Sincerely,
`
`PHARMAeiA‘a‘; Ul’JOHN COMPANY
`
`‘
`