RFRD
`
`E LA
`
`ADREEARH
`
`APPLIQATIQE N UMBER: NDA 29845
`
`QHEMIS I BY REYIESMS]
`
`
`
`

`

`NDAZO-Btlsgeviewihi
`
`
`NDA #:
`
`20-845
`
`REVIEW #:
`
`4
`
`PAGEI
`
`flLZAt/Lg
`“W l 8 1999
`
`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`Review of Chemistry. Manufacturing, and Controls
`
`DATE REVIEWED:
`
`10-Nov-99
`
`REVIEWER: JV Advani
`
`ASSIGNED DATE
`CDER DATE
`SUBMISSION TYPE DOCUMENT DATE
`----—-——————.________________
`
`ORIGINAL
`AMENDMENT (BC)
`AMENDMENT (BC)
`AMENDMENT (BC)
`Resubmission
`(INO Therapeutics)
`AMENDMENT (BC)
`AMENDMENT (BC)
`AMENDMENT (BL)
`
`26-Feb—97
`28—Aug-97
`17-Jun-97
`16-Sep-97
`25—May—99
`
`13-Aug—99
`27—Sep-99
`06-Nov-99
`
`'
`
`——____—_
`NAME & ADDRESS OF APPLICANT: '
`
`DRUG PRODUCT NAME
`Proprietary:
`
`_
`
`»
`
`Established:
`Code Name/#:
`Chem.Type/’I‘her.Class:
`
`.
`
`'
`
`.
`
`27—Feb-97
`02—Sep-97 V
`' 19-Jun-97
`17-Sep-97
`26-May-99
`
`17-Aug—99
`28-Sep-99
`08-Nov-99
`
`03-Mar—97
`04-Sep—97
`24-Jun-97
`18—Sep—97
`04—Jun—99
`
`20-Aug—99
`30-Sep-99
`10- Nov- 99 -
`
`Inc.
`
`INOTherapeutics.
`54 Old Highway 22
`Clinton. NJ 03309 /‘
`(formerly Ohmeda PPD)’
`
`.r'
`
`Inhaled Nitric Oxide (INOmax)
`This trade name was approved by LNC
`Committee on 08/25/97
`Nitric oxide
`_CAS 10102-43-
`"'1' P
`'
`
`PHARMACOL. CATEGORYIINDICATION:
`———____—_.+__
`
`DOSAGE FORM:
`
`STRENGTHS:
`ROUTE OF ADMINISTRATION:
`Rx/OTC:
`SPECIAL PRODUCTS:
`( If yes. fill out the form for special products and
`deliver to TLA through team leader for data entry)
`CHEMICAL NAME STRUCTURAL FORMULA MOLECULAR FORMULA MOLECULAR-
`
`
`WEIGHT:
`
`HypoxemicRespiratory Failure in the Term and
`near-Tenn Newborn
`Inhaled nitric oxide mixtures (nitric‘oxide in nitrogen)
`100 ppm and 800 ppm
`Inhaled
`B Rx __ OTC
`__ Yes 8 No
`
`Chemical name:
`
`'
`
`Molecular Formula:
`
`I'NO
`
`Nitric oxide
`
`Nitrogen (II) oxide
`
`Molecular Weight: 30.006
`
`

`

`EDA 20—§4§ Review #4
`
`.
`
`_
`
`.
`
`PAGE 2
`
`SQPPORTINQ DOQLJMENTS:
`
`—__'WWWW_—
`
`WW WE"
`
`
`
` Seamless. high pressure
`
`
`steel Cylinders
`
`(Vol. 1.1p0104-0106)
`
` DMF
`High pressure, diaphragm
`
`
`seal. stainless steel
`
`valve.
`(Vol. 1.1, p. 0107-01088)
`O-rings
`
`
`
`
`”up...-
`
`* Firm has provided the necessary information in the submission.
`
`RELATED DOCUMENTS {if applicable[:
`IND" .
`(Inhaled Nitric oxide—IND)
`IND
`Jnhaled — INO)
`
`‘
`
`‘
`
`‘
`
`CONSULTS:
`None
`‘
`
`REMARKS/COMMENTS:
`.
`.
`INOmax is a potent selective pulmonary vasodiiator with minimal systemic cardiovascular effects. The drug
`product is composed of Nitric Oxide (NO) in Ni'rogen (N2) at concentration of either 100 ppm or 800 ppm. It is
`packaged in aluminum cylinders fitted with a stainless steel valve seated with a Teflon O-ring.
`An EER for the establishment of Port Allen, LA, site was requested on 6/ 15/99 and it is acceptable.
`Expiration date: 36 months is proposed. 24 months stability data is provided and 30 months expiration date is
`'
`acceptable.Methods validation will be requested to be pegformed by district laboratories.
`Amendment of 11/06/99- Firm has submitted on our request the proposed draft labels for cylinders, and |
`for cardboard cylinder box. Also has included the pictures of size 88 cylinders and shrink wrap-plastic
`which will be placed around each cylinder;
`‘
`,
`CONCLUSIONS 8.- RECOMMENDATIONS:
`The information on the draft cepies of the labels for drug packages and product is reviewed and is satisfactory.
`However, we recommend the following storage statement in the labels.
`Store at 25°C (77° F) with excursions permitted between 15-30°C (SQ-86°F) (see USP Controlled Room
`Temperature). Container labels (gas cylinders) have now been provided and reviewed.
`The NBA may be approved from a chemistry viewpoint. The firm should be informed in the action letter that a
`30 month expiration date can be granted for the drug product stogeclat 25° C temperature. And recommended I
`storage statements should be included in the package insert andjabe 5
`,~\
`.
`_ /3/
`
`cc:
`
`1:1 Advani. Review Chemist
`
`-
`
`Orig. NDA 20845
`HFD-l lO/Division File
`HFD-l 10/] ADVANI I
`HFD-llO/PM
`.
`HFD-SlO/DIVISION DIRECTOR (JSimmons)
`RID init by: KSrinivasachar
`Filename:
`‘ NDA20854BC2.DOC
`
`rHFD-S lOfTEAM LEADER
`
`h
`-
`. [3/ .
`ill / i y, ‘1’?
`
`'
`
`~
`
`
`
`

`

`NDA 20-84§ Review #3
`
`II
`
`Z‘f‘icbumfl“
`PAGE 1
`
`DIVISION'OF CARDIO-RENAL DRUG PRODUCTS
`Review of Chemistry, Manufacturing, and Controls
`
`NOV " 5 1999
`
`
`NDA #:
`
`20-345
`
`REVIEW #:
`
`3
`
`DATE REVIEWED: 21-Oct-93
`
`'
`
`REVIEWER: JV Advani
`
`ASSIGNED DATE
`' CDER DATE
`SUBMISSION TYPE DOCUMENT DATE
`———-—-—-—————____..._..____________
`
`:
`
`ORIGINAL
`AMENDMENT (BC)
`AMENDMENT (BC)
`AMENDMENT (BC)
`Resubmission
`(INO Therapeutics)
`AMENDMENT (BC) .
`AMENDMENT (BC)
`
`'
`
`2 6-Feb-97
`28-Aug—97
`17—Jun-97
`16—Sep-97
`25—May-99
`
`=13—Aug—99
`27—Sep-99
`
`NAME 8: AEDDRESS OF APPLICANT:
`
`:
`
`;
`
`~
`
`2
`,
`
`“
`DRUG PRODUCT NAME
`' Proprietag:
`
`2
`
`Established:
`Code Name/#:
`ChemTypefTheLClass:
`
`PHARMACOL. CATEGORY/INDICATION:
`
`27-Feb-97
`02-Sep-97
`19—Jun-97
`17—Sep—97
`26—May-99
`
`A 17-Aug-99
`28-Sep—99
`
`'
`
`o3 -Mar—97
`04—Sep-97
`24—Jun-97
`18-Sep—97
`04—Jun—99
`
`20—Aug—99
`30-Sep-99,
`
`Inc .
`
`IND Therapeutics,
`54 Old Highway 22
`Clinton, NJ 08809
`(formerly Ohmeda PPD)
`
`-
`
`Inhaled Nitric Oxide (lNOmax)
`This trade name was approved by LNC
`:Committee on 08/25/97
`Nitric oxide
`CAS 10102-43-9
`I P
`
`Hypoxemic Respiratory Failure in the Term and
`near-Term Newborn
`Inhaled nitric oxide mixtures (nitric oxide in nitrogen)“
`
`
`DOSAGE FORM:
`
`STRENGTHS:
`ROUTE OF ADMINISTRATION:
`Rx/OTC:
`_
`-.
`SPECIAL PRODUCTS:
`( If yes, fill out the form for special products and
`deliver to TIA through team leader for data entry)
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR
`WEIGHT:
`
`100 ppm and 800 ppm
`Inhaled
`B Rx _ OTC
`, _ Yes E No
`
`‘
`
`Chemical name:
`
`‘-
`
`Nitric oxide
`
`Nitrogen (II) oxide
`
`Molecular Formula:
`
`NO "
`
`Molecular Weight: 30.006
`
`
`
`

`

`NDA 20-845 Review E;
`
`.
`
`PAGE 2
`
`fiUPPQRTING DocngN'rsr
`
`Review Letter
`
`ate
`
`Dae ,,,
`
`
`
`steel Cylinders
`(Vol. 1.1p0104-0106)
`High pressure. diaphragm
`seal. stainless steel
`valve.
`
`(Vol. 1.1, p. 0107-01088)
`O-rings
`
`-
`
`'
`
`_
`
`* Firm has’provided the necessary information in the submission.
`
`RELATED DOCUMENTS (if applicable):
`1ND
`(Inhaled Nitric oxide - lNO)
`IND
`(Inhaled — INO)
`
`CONSULTS:
`None
`
`'
`
`'3'
`
`REMARKS/COMMENTS:
`INOmax is a potent selective pulmonary vasodilator with minimal systemic cardiovascular effects. The drug
`product is composed of Nitric Oxide (NO) in Nirogen (N2) at concentration of either 100 ppm or 800 ppm. It is
`packaged in aluminum cylinders fitted with a stainless steel valve seated with a Teflon
`O-ring.
`‘
`An EER (for the establishment of Port Allen. LA. site was requested on 6/15/99 and it is acceptable.
`Expiration date: 36 months is proposed. 24 months stability data is provided and 30 months expiration date is
`acceptable.
`Methods validation will be requested to be performed by district laboratories.
`
`‘ CONCLUSIONS & RECOMMENDATIONS:
`The information submitted in this resubmission has been previously reviewed (refer to my 2 reviews). The firm
`has addressed our recommendations that were made during the 1997 submission (refer to review #2 of 10/07/97).
`
`
`
`

`

`
`
`ND'A 20-845 Review #3
`
`7.
`
`PAGE 3
`
`n
`
`We recommend the following storage statement in the package insert:
`Store at 25°C (77° F) with excursions permitted between 15-30°C (59-‘86°F) (see USP Controlled Room
`Temperature)"
`'
`The NBA may be approved from a chemistry viewpoint. The firm should be infoxmed in the action letter that a
`30 month expiration date can be granted for the drug product stored at 25° C temperature. Also Container labels
`(gas cylinder) should be provided.
`.1 Q
`
`’ '
`
`'
`
`/8/ ,
`' JV Advani. Review Chemist
`
`cc:
`
`Orig. NDA 20345
`HIFD-I IO/Division File
`
`=
`
`HFD-l 10/1ApVANI l
`HFD-l lOfPM
`
`HFD-S I OITEAM LEADER
`
`-
`
`5
`
`HFD-SlO/DIVISION DIRECTOR (JSimmons)
`RID init by: KSrinivasachar
`n %'
`Filename:
`NDA20854BC
`l
`i I I S I it" I
`
`,
`
`
`
`

`

`
`
`2..an
`
`OCT
`
`7199?
`
`-_
`
`DIVISION OF CARDIO-RENBL DRUG PRODUCTS
`Review of Chemistry, Manufacturing, and Controls
`
`NUA a:
`
`20-845 enammmw :
`
`2
`
`man: DATE:’
`
`2-Oct-9'I
`
`SUBMISSION ms DOCUMENT OATS
`
`cuss: DATE .
`
`ASSIGNED DATE:
`
`,
`ORIGINAL
`(BC)
`Amendment
`(BC)
`Amendment
`Amendment (30)
`
`26-Feb-97
`28-Aug~97
`11-Jun-97
`16-Sep-97
`
`NAME I. ADDRESS OF APPLICANT:
`
`DRUG PRODUCT NAME
`
`27-Feb-97 '
`02-§ep-97
`19-Jun-97
`17-Sep—97
`
`-
`
`03-Mar-97
`04-Sep-91
`. 24—Jun-97
`13-Sep-97
`
`OHMSOA Inc."
`Pharmaceutical Products Division ‘
`110 Allen Road
`' P.O. Box 804
`Liberty Corner, NJ 07938-0804
`
`Proprietary:
`
`II
`
`Inhaled Nitric Oxide (INOmaxF” )
`This new trade name was approved
`by LN committee on 8/25/97.
`
`NongroprietarleShN:
`Code Namefifi:
`Chem.Type(Ther.c1ass:.
`
`Nitric Oxide
`OAS l0102~43~9
`1
`P
`
`'
`
`1
`
`_
`
`PHARMACOL.CATEGORYZINDICATION:
`
`Selective respiratory hypoxia for
`treatment of persistent pulmonary
`hypertension and respiratory distress
`syndrome in the new born.
`
`STRENGTHS:
`
`I
`
`‘-
`“
`
`ROUTE 01-" ADMINISTRATION:
`DISPENSED:
`
`100 anEBoo ppm
`
`Inhaled
`
`x
`Rx
`
`OTC
`
`CHEMICAL NAME MOLECULAR FORMULA MOLECULAR WEIGHT:
`STRUCTURAL FORMULA
`—————L‘—'_———h_—‘—_f—w_——.‘_—_
`
`Chemical namegs}:
`
`'
`
`Nitric oxide
`Nitrogen (II) oxide
`
`Molecular Formula:
`SUPPORTING DOCUMENTS:
`
`NO
`
`Molecular Weight: 30.006
`
`(Inhaled Nitric Oxide - INO}
`INDr’
`J‘ Inhaled - INO)
`_
`IND
`Drug Master Files: 2
`'
`DMFr-
`DMF
`DMF
`'
`* provided on our request (refer amendment of 6/f7/97).
`
`‘
`
`A
`
`'
`
`f —
`
`-
`
`RELATED DOCUMENTS (if applicable):
`
`Literature references are provided
`
`
`
`

`

`N20-345/2
`
`-
`
`‘
`
`.
`
`‘
`
`page 2
`
`CONSULTS : None .
`
`REMARKS Z COWS R
`
`
`
`Firm has submitted original NBA (under section 505 (b)(2) of the act for an
`orphan drug}, for I-NO (Nitric Oxide) for Inhalation, 400 ppm (in nitrogen),
`packaged in size 88 (960 cu. in.) and size (l72'cu.
`in.) seamless aluminum
`. compressed gas cylinder with stainless steel valve and Teflon gasket:
`The drug product is administered using an inhalation system, at a recommended
`concentration of 20 ppm by dilution-with air/oxygen for treatment of hypoxia
`respiratory failure in term and near-term infants.
`
`Amendment of 8/28/97 provides for the 100 ppm (packaged in size D) and 800 ppm
`nitric oxide (packaged in sizes 3 and BB ) cylinders in place of the 400 ppm‘
`cylinders submitted in original NBA package of 2/26/97.
`
`-
`
`Amendment of 6/17/é5 is the response to the cue deficiencies of our letter of
`4/28/97.
`,
`.
`'
`-
`
`Amendment of 09/16/97 is in response to my telephone conference with the firm
`on 09/15/97. Accordingly they have provided updated respond to comment #3 from
`the deficiency letter of 4/28/97. Also Firm will correct the oxygen
`concentration values (FiOZ) shown in the package insert.
`
`Inhaled nitric oxide has_not been marketed or withdrawn from any country.
`Drug substance nitric oxide and drug product - inhaledrnitric oxide mixtures
`B
`will be manufactured, packaged, tested, and labeled at
`oc Gases, Port Allen,
`LA .
`J
`'
`':;-
`CONCLUSIONS & RECOlfl-IEN'DATIONS:
`
`Deficiencies noted in the review #1} have been addressed in firm's letter of
`6/17/97.
`"
`4
`Firm in separate submission will correct the Fi02 values in the package
`insert. Firm will be asked to include chemical name next to the structure
`formula and also include all inactive ingredients (N2).
`All other issues in CHC are resolved.
`Methods validation package was send out to district laboratory on 7/17/97.
`Firm has withdrawn this NDA (letter of 9/16/97) and intend to file again
`within 6 to 9 months.
`
`'
`
`CC:
`
`.
`
`Orig. NDA 20-845
`HFD-llO/Division File
`HFD-llO/JV Advani/lO/02/97
`HFD—llO/CSO
`HFD-BlO/c Hoiberg
`
`\\
`
`R/D Init. by: SUPERVISOR
`.
`
`\\
`i" and” -
`
`Advani, ReView Chemist
`f lename:
`20-845.2.NDA
`
`
`
`l
`
`

`

`Zion; bi
`
`u
`
`DIVISION OF ChRDIO-RENAL DRUG PRODUOTB
`Review of Chemistry, Manufacturing, and Controls
`
`want:
`
`20-845 cm.m;g g;
`
`1
`
`BEEIEW DATE:
`
`10-April-97
`
`SUBMISSION rrpg
`
`DOCUMENT oars
`
`CDER DATE
`
`ASSIGNED DATE
`
`APRlslgg'r
`
`ORIGINAL
`
`25-Feb-97
`
`NAME E ADDRESS OF APPLICANT!
`
`d?I
`.7,
`
`DRUG pnonucr NAME
`
`Progrietagx;
`
`gongrogrietagxzusgflz
`
`27-Feb-97
`
`03-Mar-97
`
`-
`
`OHMEDA Inc.
`Pharmaceutical Products Division
`110 Allen Road
`P.o. Box 804
`Liberty Corner, NJ 07938-0804
`
`'13
`
`_‘
`
`Inhaled Nitric Oxide (I-NO)
`Nitric Oxide
`
`.0
`
`Code Name[£:=
`
`OAS 10102-43-9
`
`.
`Chem.Ter[1her.c;ass:,
`
`1 P
`
`Selective respiratory hypoxia for
`treatment of persistent pulmonary
`hypertension and respiratory distress
`syndrome in the new born.
`400 t 20 ppm
`'
`
`Inhaled
`
`g
`
`_3;
`
`
`. orc
`
`PEARHACOL Johnson; INDICATION:
`
`m R
`
`OUTE OF ADMINISTRATION:
`
`DISPENSED:
`
`CHEMICAL NAME MOLECULAR FORMULA HOiECULAR WEIGHT:
`- STRUCTURAL FORMULA
`r—________“___..____¢.._____________4g___u..____________4_________u_.______._
`
`Ir
`
`'
`
`NO
`
`chemical name{s):-
`
`. Nitric oxide
`Nitrogen (II) oxide
`
`‘Moleculsr Formula:
`
`No
`
`SUPPORTING DOCUMENTS:
`
`Molecular Weight: 30.006
`
`(Inhaled Nitric Oxide — 1N0)
`INDr
`‘)(Inheled - IND)
`IND
`ngg Master Files:
`
`ourf
`our
`our
`
`RELATED DOCUMENTS {if anglicahle):
`
`Literature references are provided
`
`CONSULTS: None.
`
`vmy.
`
`
`
`“reronj“7""
`
`

`

`I
`
`‘
`
`RDA 20-345 Review E!
`
`'
`
`I
`
`_
`
`page 2
`
`REMARKS COMMENTS:
`
`-
`
`'
`
`Firm has submitted this'NDA {under section 505 (b)(2j of the act for an orphan
`drug). for —No (Nitric Oxide) for Inhalation, 400 ppm (in nitrogen), packaged
`in size 88 (960 cu.
`in.) and size (172 cu. in,) seamless aluminum compressed
`gas cylinder with stainless steel valve and Teflon5gasket.
`The drug product is administered using an inhalation system. at a réiommended
`concentration of 20 ppm by dilution with air/oxygen for treatment of hypaxic
`respiratory failure in term and near-term infants.
`
`Inhaled nitric oxide has not been marketed or withdrawn from any country;
`Drug substance nitric oxide and drug product - inhaled nitric oxide mixtures
`will be manufactured, packaged, tested, and labeled atrBoc Gases, Port Allen,
`LA.
`
`CONCLUSIONS 8 RECOMMENDATIONS:
`
`Deficienciés noted in the review, have been summarized in the draft of the
`controls portion of the letter to the applicant.
`
`ur-
`
`1
`
`cc:
`
`5
`
`.
`
`Orig. NDA- 20-845
`HFD-llO/Division File
`HFD-llO/JV Advani/4/14/97
`syn-110 [cso
`HFD-BlO/C. Hoiberg
`
`-_
`
`-
`
`’
`a
`
`.
`
`.
`R/D Init. by: SUPERVISOR
`_
`
`‘
`re—e
`
`\l
`
`(\
`a;
`
`_
`
`I
`JV Advani,‘ Review Chemist
`fi ename:
`-20-845.NDA
`
`/S/
`
`Mun——
`
`;
`
`
`
`
`
`