CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022523Orig1s000
`
`
`OTHER REVIEW(S)
`
`
`
`
`

`

`
`
`
`
`
`Application Number:
`
`Name of Drug:
`
`Sponsor:
`
`
`
`
`
`
`
`Material Reviewed:
`
`PROJECT MANAGER’S REVIEW
`
`
`
`NDA 22-523
`
`PANCREAZE™ (Pancrelipase Capsules)
`
`Johnson and Johnson Pharmaceutical Research &
`Development, L.L.C.
`
`PANCREAZE™ (Pancrelipase) Delayed-Release Capsules
`Carton and Container Labels
`
`
`June 23, 2009, November 19, 2009, April 7, 2010
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`
`
`Office of Biotechnology Products
`Federal Research Center
`Silver Spring, MD
`Tel. 301-796-4242
`
`
`
`
`Memorandum
`
`
`
`OBP Receipt Date:
`
`
`EXECUTIVE SUMMARY
`
`
`The carton and container labels for PANCREAZE™ (Pancrelipase) Delayed-Release
`Capsules were reviewed and found to comply with the following regulations : 21 CFR
`201.2 through 21 CFR 201.25; 21 CFR 201.50 through 21 CFR 201.57, 21 CFR 200.100
`and United States Pharmacopoeia, 12/1/09-5/1/10, USP 32/NF 27. Labeling deficiencies
`were identified and mitigated. Please see comments in the conclusions section. The
`revised carton and container labels are acceptable.
`
`
`
`Background:
`
`PANCREAZE™ (Pancrelipase) Delayed-Release Capsules is a New Drug Application
`(NDA) indicated as a combination of porcine-derived lipases, proteases, and amylases
`indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or
`other conditions.
`
`Labels Reviewed:
`PANCREAZE® (Pancrelipase) Container Label
`
`4,200 Lipase Units -100 ct Trade Bottle
` 21,000 Lipase Units -100 ct Trade Bottle
`
`

`

`NDA 22-523 Page 2 of 13
`
`16,800 Lipase Units -100 ct Trade Bottle
`
`10,500 Lipase Units -100 ct Trade Bottle
`
`
`
`PANCREAZE® (Pancrelipase) Carton Label
`
`4,200 Lipase Units -100 ct Trade Bottle
` 21,000 Lipase Units -100 ct Trade Bottle
`
`16,800 Lipase Units -100 ct Trade Bottle
`
`10,500 Lipase Units -100 ct Trade Bottle
`
`
`
`
`
`Review
`The carton and container labels for PANCREAZE® (Pancrelipase) were reviewed using
`the following regulations: 21 CFR 201.1 through 21 CFR 201.18; 21 CFR 201.25; and
`21 CFR 201.50 through 21 CFR 201.55 through 21 CFR 200.57; 21 CFR 201.100 and
`United States Pharmacopeia, 12/1/10-5/1/10, USP 32/NF27. Please see comments in the
`conclusions section.
`
`I. Container
`
`
`A. Bottle Label
`1.
`21 CFR 201.1 Drugs; name and place of business of manufacturer,
`packer or distributor-
`Manufactured By: Nordmark Arzneimittel GmbH & Co. KG
`25436 Uetersen, Germany
`Manufactured for: McNeil Pediatrics, Division of Ortho-McNeil-
`Jansen Pharmaceuticals, Inc. Titusville, NJ 08560
`This conforms to the regulation.
`
`21 CFR 201.2 Drugs and devices; National Drug Code numbers-
`The National Drug Code (NDC) number is located above the
`proprietary name at the top of the label. It is noted as NDC 50458-
`XXX-60. The NDC number conforms to 21 CFR 207.35 as a 3-2
`Product-Package Code configuration. This conforms to the
`regulation.
`
`2.
`
`
`3.
`
`21 CFR 201.5 Drugs; adequate directions for use-On the left of the
`label “For dosage and other prescribing information, see
`accompanying product literature.” appears on the container labels.
`This conforms to the regulation.
`
`21 CFR 201.6 Drugs; misleading statements- The proprietary name
`PANCREAZE™ appears on the label with the established name,
`pancrelipase. This conforms to the regulation.
`
`21 CFR 201.10 Drugs; statement of ingredients- The established
`
`
`4.
`
`
`5.
`
`

`

`NDA 22-523 Page 3 of 13
`
`
`
`name, Pancrelipase is not used in type at least half as large as the
`most prominent presentation of the proprietary name,
`PANCREAZE®. This does not conform to the regulation.
`
`21 CFR 201.15 Drugs; prominence of required label statements-
` All required statements (“Rx Only” and “Protect from Moisture”)
`appear on the label. “Protect from Moisture” and “Avoid excessive
`heat” do not appear on the label. This does not conform to the
`regulation.
`
`21 CFR 201.17 Drugs: location of expiration date-The expiration
`date appears under the lot identification number on the right side of
`the label. This conforms to the regulation.
`
`
`6.
`
`
`
`7.
`
`8.
`21 CFR 201.25 Bar code label requirements – The bar code is
` located on the left of the label with sufficient white space
`surrounding to ensure for proper scanning. This conforms to the
`regulation.
`
`21 CFR 201.50 Statement of identity- The ingredients, Lipase,
`Amylase and Protease are listed with corresponding units per
`capsule per 21 CFR 201.10. This conforms to the regulation.
`
`9.
`
`
`10.
`
`
`11.
`
`
`12.
`
`
`13.
`
`21 CFR 201.51 Declaration of net quantity of contents – The label
`prominently states the net quantity of contents in terms of
`numerical count in units on the label, below the proprietary and
`established name. This conforms to the regulation.
`
`21 CFR 201.55 Statement of dosage- On the left of the label “For
`dosage and other prescribing information, see accompanying
`product literature.” appears on the container labels. This conforms
`to the regulation.
`
`21 CFR 201.100 Prescription drugs for human use- The label bears
`statements “Rx Only”, identifying lot number, storage conditions
`and a reference to the package insert. “Protect from Moisture” and
`“Avoid excessive heat” are not listed on the label. This does not
`conform to the regulation.
`
`21 CFR 208.24 Distribution and dispensing of a Medication guide-
`If a Medication Guide is required under part 208 of chapter, the
`statement required under §208.24(d) of this chapter instructing the
`authorized dispenser to provide a Medication Guide to each patient
`to whom the drug is dispensed and stating how the Medication
`Guide is provided, except where the container label is too small,
`the required statement may be placed on the package label. This
`conforms to the regulation.
`
`1 Page(s) has (have) been Withheld in
`Full immediately following this page as
`B4 (CCI/TS)
`
`

`

`NDA 22-523 Page 5 of 13
`
`II. Carton
`1.
`
`
`
`
`
`
`
`
`
`2.
`
`3.
`
`4.
`
`
`5.
`
`
`
`21 CFR 201.1 Drugs; name and place of business of manufacturer,
`packer, or distributor- The label states:
`Manufactured By: Nordmark Arzneimittel GmbH & Co. KG
`25436 Uetersen, Germany
`Manufactured for: McNeil Pediatrics, Division of Ortho-McNeil-
`Jansen Pharmaceuticals, Inc. Titusville, NJ 08560
`This conforms to the regulation.
`
`21 CFR 201.2 Drugs and devices; National Drug Code numbers-
`The National Drug Code (NDC) number is located above the
`proprietary name at the top of the label. It is noted as NDC 50458-
`XXX-60. The NDC number conforms to 21 CFR 207.35 as a 3-2
`Product-Package Code configuration. This conforms to the
`regulation.
`
`21 CFR 201.5 Drugs; adequate directions for use-On the left of the
`label “For dosage and other prescribing information, see
`accompanying product literature.” appears on the container labels.
`This conforms to the regulation.
`
`21 CFR 201.6 Drugs; misleading statements - The proprietary
`name, PANCREAZE™ appears with the established name,
`pancrelipase on the carton. This conforms to the regulation.
`
`21 CFR 201.10 Drugs; statement of ingredients- The established
`name, Pancrelipase is not used in type at least half as large as the
`most prominent presentation of the proprietary name,
`PANCREAZE®. This does not conform to the regulation.
`
`
`(b) (4)
`
`

`

`NDA 22-523 Page 6 of 13
`
`
`
`
`
`
`
`
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`
`12.
`
`
`13.
`
`21 CFR 201.15 Drugs; prominence of required label statements-
` All required statements (“Rx Only” and “Protect from Moisture”
`appear on the label. “Protect from Moisture” and “Avoid excessive
`heat” do not appear on the label. This does not conform to the
`regulation.
`
`
`21 CFR 201.17 Drugs; location of expiration date - The expiration
`date appears on the carton below the lot number. This conforms to
`the regulation.
`
`21 CFR 201.25 Bar code label requirements - The bar code is
`located at the bottom of the back panel of the carton with sufficient
`white space surrounding to ensure for proper scanning. This
`conforms to the regulation.
`
`21 CFR 201.50 Statement of identity - The ingredients, Lipase,
`Amylase and Protease are listed with corresponding units per
`capsule per 21 CFR 201.10. This conforms to the regulation.
`
`21 CFR 201.51 Declaration of net quantity of contents - The label
`does state the net quantity of contents in terms of numerical count
`in units at the top of the carton. This conforms to the regulation.
`
`21 CFR 201.55 Statement of dosage - The label states “For dosage
`and other prescribing information, see accompanying product
`literature. This conforms to the regulation.
`
`21 CFR 201.100 Prescription drugs for human use - The label
`bears statements for “Rx Only”, an identifying lot number, storage
`conditions, and a reference to the package insert. “Protect from
`Moisture” and “Avoid excessive heat” are not listed on the label.
`This does not conform to the regulation.
`
`21 CFR 208.24 Distribution and dispensing of a Medication guide-
`If a Medication Guide is required under part 208 of chapter, the
`statement required under §208.24(d) of this chapter instructing the
`authorized dispenser to provide a Medication Guide to each patient
`to whom the drug is dispensed and stating how the Medication
`Guide is provided, except where the container label is too small,
`the required statement may be placed on the package label. This
`conforms to the regulation.
`
`III.
`
`
` National Stock Number
`1.
`Discussed the presentation of the NSN with the Chief of Quality of
`Assurance, Health and Human Services Supply Service Center,
`Program Support Center, Perry Point, Annette Quinones, 410-642-
`1386 on March 26, 2010 (NSN) 6505-01-287-2XXX, listed on the
`
`

`

`NDA 22-523 Page 7 of 13
`
`container and carton labels for commercial use. Ms. Quinones
`informed me that the NSN is an internal government identification
`that is used on prescription products that are repackaged at Perry
`Point for government institutional use. The NSN number should
`be omitted from commercial prescription drug product labels.
`
`
`
`Labels submitted November 19, 2009
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`1 Page(s) has (have) been Withheld in
`Full immediately following this page as
`B4 (CCI/TS)
`
`

`

`NDA 22-523 Page 9 of 13
`
`
`Labels submitted April 6, 2010
`Container labels
`
`
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`NDA 22-523 Page 10 of 13
`NDA 22-523
`Page 10 of 13
`
`
`q,
`
`Fordosageanc other
`[5);sz IQIIIOIITIWIWUO'L
`product liteliatulle.g
`C)
`Keep out of reach
`E o‘cl‘ilrlren.
`V
`("I3
`GO
`Ln
`1
`8
`
`2 n
`
`NDC 50453-34260
`PANCREAZET”
`.
`{pancrellpase}
`
`Delayed-Release Capsules
`.
`.
`E300 capsule contalns.
`pane
`U
`10'5“) USP Ulits
`Amylase 43.750 USP UNITS
`Protease 25.000 USP Units
`
`
`
`
`
`DOSE BY LIPASE UNITS
`Attention Pharmacist: Dispense the
`accompapying Medication Guide to
`93¢“ Dfltlem-
`
`100 capsules
`
`\
`
`
`
`LOT:
`EXP:
`Each capsule contains erlteric
`coated pancrelipase microtablets.
`To prhotgct enlterigoating, microtablets should not be
`”"5 e 0' c 9‘"
`'
`Avoid heat. PANCREAZE'” hard gelatin capsules should be
`stored in a dry place in the original container. After opening.
`KEEP THE CONTAINER TIGHTLY CLOSED between uses
`to PROTECT FROM MOISTURE. Do not store above 95°c
`[WP].
`Manufactured by: Nordmark Arzneirnittel (3th 8. Co. KG
`25436 Uetersen. Germany
`Manufactured for: McNeil Pediatrics.
`Division of Ortho-McNeiI-Jahssen Pharmaceuticals, Inc.
`Ti‘tusville. NJ 08560
`
`Egonty.
`c ow PI 2010
`AW_531 10
`
`
`
`
`
`[54005094]! 103 1
`
`
`
`
`N DC 50458-343-60
`LOT:
`
`EXP:
`Each capsule contains enteric
`For dosage and other
`PANCREA-ZE
`
`[pancrellpasel
`Prflcrlb'ng Infotmfltlon-
`coated pancrelipase microtablets.
`D |
`d P.
`|
`C
`|
`see accompanying
`,
`.
`.
`
`
`9 Bye ' 9 9359 Eleu es
`To protect enter": coating. microtahlets should not be
`E 0 product lltcraturc.
`_
`_
`Keep out of reach
`crushed or chewed.
`(0
`
`Avoid heat. PAI'NICFIEAZE'M hard gelatin capsules should be
`E l
`of children.
`EaCh capsule CO ntalns.
`KEEP THE CONTAINER TIGHTLY CLOSED between uses
`.
`3 — stored in a drl.I place in the original container. After opening.
`
`0:)
`Amylase T0300 USP UNIS
`to PROTECT FFlOM MOISTURE. Do not store above 25°C
`a)
`Protease 40,000 USP Units
`IYT’FI.
`L0
`Manufactured by: Nordn'lark Arznelmittel GmbH 5. Co. KG
`
`‘EI'
`25436 Uetersen. Germany
`
`8
`Manufactured for: McNeil Pediatrics,
`Division of Ortho-McNeil-danssen Pharmaceuticals. Inc.
`Titusville. NJ 05550
`B. only.
`Z (‘0
`as OMJPI 2010
`
`AW_53111
`
`TM
`
`
`
`
`
`DOSE BY LIPASE UNITS
`Attention Pl'armaci.“ gimme
`accompanlnna Medication GUIdE 110
`9“" PI‘IEM-
`
`100 capsules
`
`N0050943 106
`
`
`
`
`
`
`K
`
`C\|
`
`NDC 50458-345—60
`
`LOT:
`
`\
`
`EXP:
`
`
` IIIIIIIIIIII
`
`
`
`DOSE BY LIPASE UNITS
`Attention Pharmacist: Dispense the
`accompanying Medication Guide to
`each patient.
`
`100 capsules
`
`
`
`N0050949 109 1
`
`
`For dosage and other
`prescribing information,
`see accorr parying
`product literature.
`Keep out of reach
`of children.
`
`I’ANCREAZETM
`{pancrelipase}
`Delayed-Release Capsules
`
`
`
` Each capsule contains:Protease 3?.000 USP Units
`
`Amylase 61,000 USP Units
`
`Each capsule contains entenc
`coated pancrelipase microtablets.
`To protect enteric coating. microtablets should not be
`crushed or chewed.
`Avoid heat. PANCREAZE‘“ hard gelatin capsules should be
`stored in a dry place in the original container. After opening,
`KEEP THE CONTAINER TIGHTLY CLOSED between uses
`to PROTECT FROM MOISTURE. Do not store above 25°C
`[WP].
`Manufactured by: Nordmark Arzneimittel (3th a Co. KG
`25436 Uetersen. Germany
`Manufactured for: McNeil Pediatrics.
`Division of Ortho-McNeiI-danssen Pharmaceuticals. Inc.
`Titusville. NJ 08560
`1}, only.
`It? OMJ Pi 2010
`AWJ3‘I 12
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 22-523 Page 11 of 13
`NDA 22-523
`Page 11 of 13
`
`Cartons
`Cartons
`
` mun-m HUDIIW' Wfllofl
`
`
`(antennae-GI
`mi-IZVEHIDN \fd
`
`
`IdXEI
`
`
`LLO‘I
`III
`
`
`
`unr. Manama
`PANCR E AZ E"
`PA NCREAZE'“
`PANCREAZE'“
`PA NCREAZE'“
`
` u Cnnlulu nolnwmnolnnn cannula
`
`
`telnerollnen}
`lunnerfliuu}
`lunmlin
`)
`Inlncnliflu]
`
`
`Del-MAE .
`mayeu—Role-nn Gan-LII”
`Delayed—Helene. cannula-
`
`
`
`Anulflon Puma-mu: Dim-In IM
`
`Each ceDwIe nonlelne'
`mun-mm lmm :-
`
`uneh gum
`
`
`
`—Arnyiase .600 USP Unlla
`fwamm nrlwu‘n-muw w.m.
`
`.-mm mun.
`
`
`
`1am m “an,“uum
`
`Protease 1mm USP unlle
`m u: um an am
`mm mm. rvwclluur. -- run-.1 awn unu—
`
`
`
`un...“ n- Mn. m. nun-numer—
`DOSE BY UPASE UNITS
`euw-u Ann moon. IEEII ml: mum
`mam: cmu mum. “- b mares:
`um mnvunc. D: m m.- lbw- w:
`
`
`
`(H‘Il.
`Each capsule coma-nu lmnflc
`
`canted urinal-Elna“ mlclulnblatl.
`«null cu! a: much a gum-w.
`
`mull-June! Hr
`mm Almflfl men .1 Eu. m:
`
`
`Ann-mm mum-mm:
`yuan use"... urn-um
`
`WMMIw-{l nu.
`
`
`Dun-Inn m “comp-flying
`w»- Humour-0|. Bum-or
`male-m num- m “can
`
`onmwnmw fiw-IWMO. Inc
`Elli-all.
`
`
`
`
`
`Handy-
`(-32
`
`
`
`
`
`
`NDDSSS‘IZ
`! FASEHHIC HT$
`KVE 450
`
`
`50458 -34 1 - o—
`
`
`
`
`
`
`
`
`
`
`mun" “Ii-Ilvfll‘lI-fl
`(“gull-mung;
`”3'2!" EHDNVA
`:an{1.01
`III
`
`
`PANCR EAZE”
`ludnqullfluu}
`LIuI-yuchflumw can-um.
`All-nun“ ram-u: nun-n— m.
`mwwwmo um» cum-1o
`"an nun-nL
`:5. m m m.- pun-m.“
`Imam-Hun. “mu-Ind"! wanna
`"mm".
`1bmm nan-me,mmin m “on“ «mm-m.
`a.“ mm. mm"- m on...“
`«own-- Mob-mum - .w u.- u.
`
`ur- wan-I www.mu cam-m K:
`mr. mun-n nun-rm quorum
`u... -.. moves! s m lac-smut. on. «x
`“mm :n-mn-n.
`my uul o- wnul ”n.4,,
`MIr-ulbc‘u'wd by
`an...“ ~........_- 9...... . ‘3. MI
`93.4.1: Hum-m. MW
`er-ulbdwuu n-
`m"... mm"... 5......
`anhau-McNmH-n-l-n mum... m;
`Ynmwmmm
`cowl-.n‘o
`
`4
`3
`II
`I‘ ma 'knq
`604 5 8 «342-60
`
` DCH I'
`
`
`
`PANCR EAZE"
`lunar-luau.)
`Lumyvumu-uuu Gulliul-l
`Each can-Mule cor-mains:
`wlem «3.750 USP uruua
`_Ffi'oiom 25.000 USP Ur‘ila
`DOSEBYM ums
`“mun... finnmn- can“ emu-n
`pnncr-l'fln- flaw-Elvin.
`W W“:
`nap-n.- “vim-Flyin-
`mm m w mum-n.
`
`35W
`
`I’A NCKEAZ E'“
`
`(am-walnu-(bu'nyul-Hu'du- .umn
`
`Nun sen:
`
`KVF. Am
`
`PANC Ill-:Az E”
`[Puritan-01W I'll
`bullyul-H-Iom- cumulu-
`
`
`
`

`

`NDA 22-523 Page 12 of 13
`NDA 22-523
`Page 12 of 13
`
`nun-duo Omani-bu
`(“nun-mum]
`..'!IV3II'.'INV¢I
`
`
`
`III
`
`
`
`
`NBC mam-an
`PANCREAIE'"
`PANCREAZE‘"
`PANCIIEAZE"
`
`mnmflnnal
`Immnlipnm
`(panenlnlul
`
`
`
`Bohr-avfillllm Baum
`n-I-mm. Gland“
`balmy-availing Caligula:
`mum-mammar-
`
`Wang-mum»
`mwmm:
`gun-nun.
`
`
`memwnmmnwuWmmm
`
`Mum.
`
`Amy-1m 70.000 USP Unite
`
`
`hmmmm
`
`{EN-clans. 40M USPUr!ta__
`magma-mum
`
`mmmr-mmm
`DOSE BY ”RISE UNITS
`
`
`mmmn-mmmmm
`
`W. anuwnttvmaoww-tu
`Em numb mm m mind
`
`fmfflflflwunw WORK)!
`Fnouumluas.mm nan-mayo
`amine-a min-mm
`
`
`m'FL
`mun-Influx" uranium
`
`AWW
`
`Wm—“mammal-m
`nun-n,
`
`
`
`mm
`
`
`
`
`
`
`
`3
`
`sway 3-60
`
`
`
`
`
`PANCREAIE'"
`Inna-ulna“)
`Dulwm CID-um
`
`
`
`‘
`
`
`
`\
`
`
`
`
`
`
`
`
`
`
` um.” “.qumqm
`
`on-mFm-umg
`-JZVHHDNVII
`
`1/
`\
`III
`fi
`
`FANCREAZE"
`PA NCIREAZE"
`PANCREAZE'
`PANCREAZE"
`
`I
`b-nw-Iln-Il)
`gnaw-o
`Inflnnmu-fl
`{F-nnI-ID-Id)
`
`Dm-fl‘H-m Gnu-nic-
`D-Iw-amu Gnu-MI“
`yum-m..- cu...»-
`D-I-na-u-lnu c-m—
`”truly-mum”
`momma-mam...“
`maul-alum.-
`mmrum-mun.m
`Ammm sumo us» unn-
`:mum.mmmmn
`mm 37.“ USP LINN
`wmmmm
`“mammal-Iguana.
`A...”— <MHMK'-l-—I——m
`mavmuu’rs
`wummmmlwfll‘llllm
`mummy—mun n.-
`:nr- mm- mm- n-mu: coal-ll
`ocwmun nnunw CLDHDBM‘Q—
`._m.—ums~..m.m-.
`Mme-hmun-Wmum-Am
`m...
`km
`
`L
`
`50459—34340
`
`Na
`
`I raunluufllw
`
`nun-aims
`xvl 4-:
`
`

`

`NDA 22-523 Page 13 of 13
`
`III. Conclusions
`A.
`The proposed carton and container labeling are acceptable only upon the
`following changes:
`
`
`
`1.
`
`
`
`
`
`
` 2.
`
`Per 21 CFR 201.10, please revise the presentation of the
`established name and proprietary name. The established name
`shall have the prominence commensurate with the prominence of
`the proprietary name or designation appears, taking into account all
`pertinent factors, including typography, layout, contrast, and other
`printing features. It shall also be printed in letters that are at least
`half as large as the letters comprising proprietary name. Change
`made and acceptable.
`
`Per 21 CFR 201.15 and 21 CFR 201.100 - Please add the bolded
`statements, “Protect from moisture” and “Avoid excessive heat” to
`the storage conditions listed. The statements “After opening, KEEP
`THE CONTAINER TIGHTLY CLOSED between uses to
`PROTECT FROM MOISTURE” and “Avoid heat” were added to
`the carton and container. Change acceptable.
`
`
`
`
`
`
`
`
`
`
`
`
` 3.
`
`
` 4.
`
`
`
`Per Health and Human Services Supply Service Center, Perry
`Point, Maryland, please omit National Stock Numbers (NSN) from
`the carton and container labels. Change made and acceptable.
`
`Additional revisions that are acceptable are as follows:
`a) A box was added to enclose the enzymes and corresponding
` Units.
`b) “DOSE BY LIPASE UNITS” was added directly under
` the box listing the enzymes and corresponding Units.
`
`c) The additional medication guide statement was removed from
`
`
`
` the side panel to the primary panel
`
`
`
`d) The distinguishing color for Lipase 16,800, Amylase 70,000,
`
`
`
` and Protease 40,000 was changed from an orange hue to a teal
`
`
` hue.
`
`
`
`_______________________
`Kimberly Rains, Pharm.D
`Regulatory Project Manager
`CDER/OPS/OBS
`
`
`
`
`
`
`
`
`
`
`
`Comment/Concurrence:
`
`
` ______________________________
`
`
`
`
`Barry Cherney, Ph.D.
`Howard Anderson, Ph.D.
`
`
`Deputy Director
`Product Reviewer
`
`Division of Therapeutic Proteins
`
`Division of Therapeutic Proteins
`CDER/OPS/OBP/
`
`
`
`CDER/OPS/OBP
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22523
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`------------------------------------------
`Pancrelipase Microtablets
`
`--------------------
`JOHNSON &
`JOHNSON
`PHARMACEUTICA
`L RESEARCH &
`DEVELOPMENT
`LLC
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KIMBERLY M RAINS
`04/09/2010
`
`HOWARD A ANDERSON
`04/12/2010
`
`BARRY W CHERNEY
`04/12/2010
`
`

`

`Attachment B: Sample PMR/PMC Development Template
`
`
`This template should be completed by review management and included for each PMR/PMC in the
`Action Package.
`
`
`PMR/PMC Title: Deferred requirement for development of an age appropriate formulation
`for PANCREAZE (pancrelipase) Delayed-Release Capsules to allow for
`dosing to the youngest, lowest weight pediatric patients, including infants
`less than 12 months of age who will be administered 2,000 to 4,000 lipase
`units per 120 mL of formula or per breast-feeding. Submit a supplement for
`an age appropriate formulation by October, 2012.
`
`Protocol Submission Date:
`Study Initiation Date:
`Study Completion Date:
`Final Study Report Submission Date:
`Other:
`
`
`PMR/PMC Schedule Milestones:
`
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement (e.g., unmet need, life-threatening condition, long-term data needed, only
`feasible to conduct post-approval, prior clinical experience indicates safety, small subpopulation
`affected, theoretical concern).
` The low weight pediatric patients are a small subpopulation affected.
`
`MM/DD/YYYY
`MM/DD/YYYY
`MM/DD/YYYY
`MM/DD/YYYY
`MM/DD/YYYY
`
`
`2. If required, characterize the PMR. Check all that apply and add text where indicated.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated approval
` Animal efficacy confirmatory studies
` Pediatric requirement
` FDAAA required safety study/clinical trial
`- Describe the particular review issue leading to the PMR
`In order to give the proper dose of PEPs to low weight pediatric patients, a formulation needs
`to be developed which can dose them correctly without using partial doses.
`
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 4/12/2010
`
`Page 1 of 4
`
`

`

`- If the PMR is a FDAAA safety study/clinical trial, describe the risk
`
`
` -
`
` If the PMR is a FDAAA safety study/clinical trial, does it:
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
`
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`
`3. For a post-approval FDAAA study/clinical trial, describe the new safety information
`
`
`
`4. If not required by regulation, characterize the review issue leading to this PMC
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 4/12/2010
`
`Page 2 of 4
`
`

`

`
`5. What type of study or clinical trial is required or agreed upon (describe)?
`The Sponsor agrees to develop a formulation for PANCREAZE which will allow dosing to the
`youngest, lowest weight pediatric patients who will be administered 2,000 to 4,000 lipase units per
`120 mL of formula or per breast-feeding.
`
`
`Required
` Pharmacoepidemiologic study (list risk to be evaluated)
`
` Registry studies
` Primary safety study or clinical trial (list risk to be evaluated)
`
` Subpopulation (list type)
`
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing studies
` Additional data or analysis required for a previously submitted or expected study
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Development of a specific formulation for PANCREAZE which will allow lipase doses of
`2,000 to 4,000 lipase units (per 120 mL of formula or per breast-feeding) to be administered to
`pediatric patients.
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup)
` Dose-response study performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`Development of a specific formulation for PANCREAZE which will allow lipase doses of
`2,000 to 4,000 lipase units (per 120 mL of formula or per breast-feeding) to be administered to
`pediatric patients.
`
`
`
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 4/12/2010
`
`Page 3 of 4
`
`

`

`6. Is the PMR/PMC clear and feasible?
` Are the schedule milestones and objectives clear?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, and determine
`feasibility?
`
`
`CDTL or PMR/PMC Development Coordinator:
`This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 4/12/2010
`
`Page 4 of 4
`
`

`

`Attachment B: Sample PMR/PMC Development Template
`
`
`This template should be completed by review management and included for each PMR/PMC in the
`Action Package.
`
`
`PMR/PMC Title:
`
`A 10 year, observational study to prospectively evaluate the incidence of fibrosing
`colonopathy in patients with cystic fibrosis treated with PANCREAZE
`pancrelipase) Delayed-Release Capsules in the US and to assess potential risk
`factors for the event.
`
` June, 2011
`MM/DD/YYYY
` January, 2022
` August, 2022
`MM/DD/YYYY
`
`Protocol Submission Date:
`Study Initiation Date:
`Study Completion Date:
`Final Study Report Submission Date:
`Other:
`
`
`PMR/PMC Schedule Milestones:
`
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement (e.g., unmet need, life-threatening condition, long-term data needed, only
`feasible to conduct post-approval, prior clinical experience indicates safety, small subpopulation
`affected, theoretical concern).
`The safety of PEPS is well established based on ample information available in the medical
`literature. Fibrosing colonopathy has been reported following treatment with different pancreatic
`enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in
`association with high-dose pancreatic enzyme use, usually over a prolonged period of time and
`most commonly reported in pediatric patients with cystic fibrosis.
`
`
`2. If required, characterize the PMR. Check all that apply and add text where indicated.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated approval
` Animal efficacy confirmatory studies
` Pediatric requirement
` FDAAA required safety study/clinical trial
`- Describe the particular review issue leading to the PMR
`In the drug class of Pancrelipase, there were cases of fibrosing colonopathy identified.
`
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 4/12/2010
`
`Page 1 of 4
`
`

`

`- If the PMR is a FDAAA safety study/clinical trial, describe the risk
`Fibrosing colonopathy is a serious, rare condition that has been described in association with
`high-dose pancreatic enzyme use.
`
` -
`
` If the PMR is a FDAAA safety study/clinical trial, does it:
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`
`3. For a post-approval FDAAA study/clinical trial, describe the new safety information
`Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme
`products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association
`with high-dose pancreatic enzyme use, usually over a prolonged period of time and most
`commonly reported in pediatric patients with cystic fibrosis.
`
`
`4. If not required by regulation, characterize the review issue leading to this PMC
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 4/12/2010
`
`Page 2 of 4
`
`

`

`
`5. What type of study or clinical trial is required or agreed upon (describe)?
`
`
`
`Required
` Pharmacoepidemiologic study (list risk to be evaluated)
`
` Registry studies
` Primary safety study or clinical trial (list risk to be evaluated)
`Fibrosing Colonopathy
` Subpopulation (list type)
`
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affin