LACHMAN CONSULTANT SERVICES, INC.
`CONSULTANTS TO THE PHARMACEUTICAL AND ALLIED INDUSTRIES
`
`1600 STEWART AVENUE, WESTBURY, NY 11590
`(516) 222-6222 (cid:120)(cid:120) FAX (516) 683-1887
`
`May 8, 2018
`
`VIA ELECTRONIC SUBMISSION
`
`Division of Dockets Management
`Food and Drug Administration (HFA-305)
`Department of Health and Human Services
`5630 Fishers Lane, Room 1061
`Rockville, MD 20852
`
`Dear Sir or Madam:
`
`CITIZEN PETITION
`
`The undersigned submits this petition, pursuant to Section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic
`Act, and in accordance with 21 CFR 10.30 and 21 CFR Sec. 314.93 on behalf of a client requesting the
`Commissioner of the Food and Drug Administration (FDA) to declare that Cysteine Hydrochloride Injection 5%
`containing 34.6 mg/mL of Cysteine base are suitable for consideration in an abbreviated new drug application
`(ANDA).
`
`A. Action Requested
`
`The petitioner requests that the Commissioner of the Food and Drug Administration declare that, Cysteine
`Hydrochloride Injection 5% containing 34.6 mg/mL of Cysteine base are suitable for submission as an ANDA. The
`reference-listed drug product (RLD), upon which this petition is based, is Cysteine Hydrochloride Injection 7.25%
`in syringe which is subject of NDA 19-523 most recently held by Hospira, Inc. (Hospira), and initially approved on
`October 22, 1986, as designated in the Orange Book (see copy of the page from the current Electronic Edition of the
`Approved Drug Products with Therapeutic Equivalence Evaluations (Attachment 1). On June 4, 2010, the FDA
`announced its determination that Cysteine Hydrochloride Injection, USP, 7.25%, was not withdrawn from sale for
`reasons of safety or effectiveness. This determination allows FDA to approve abbreviated new drug applications
`(ANDAs) for Cysteine Hydrochloride if all other legal and regulatory requirements are met.
`
`Statement of Grounds
`
`The Federal Food, Drug, and Cosmetic Act provides for the submission of an Abbreviated New Drug Application
`for a drug product that differs in strength that of the listed drug provided the FDA has approved a petition that
`proposed filing such an application.
`
`The RLD, held by Hospira is a sterile, nonpyrogenic solution of Cysteine Hydrochloride 7.25% containing 0.5 gram
`in 10 mL of water for injection. The petition is thus seeking a change in strength (total drug content) (from 0.5
`g/container to 0.346 g/container) from that of the RLD.
`
`Based on the original approved labeling for the RLD, for addition to amino acids solutions intended for use in
`newborn infants, it is recommended that 7.25% Cysteine Hydrochloride Injection, USP be added to the amino acids
`solution to provide cysteine at approximately 1.5% of the total amino acids. Hence, an infant receiving amino acids
`solutions at 2.5 g/kg/day should be provided 37.5 mg/kg/day of cysteine or 0.75 ml/kg/day of 7.25% Cysteine
`Hydrochloride Injection, USP. Similarly, an infant receiving amino acids solutions at 3 g/kg/day should be provided
`45 mg/kg/day of cysteine or 0.9 ml/kg/day of 7.25% Cysteine Hydrochloride Injection, USP. For addition to amino
`acids solutions that are intended for use in adults, a dosage of 5 mg of cysteine per gram of amino acids can be used.
`For example, 6 ml of 7.25% Cysteine Hydrochloride Injection, USP added to 500 ml of 11.4% Amino Acids
`Injection will provide a final concentration of 60 mg cysteine per 100 ml of amino acids solution.
`
`www.lachmanconsultants.com LCS@lachmanconsultants.com
`
`Eton Ex. 1092
`1 of 12
`
`

`

`LACHMAN CONSULTANT SERVICES, INC.
`Westbury, NY 11590
`
`Division of Dockets Management
`Food and Drug Administration
`May 8, 2018
`Page 2 of 3
`
`Therefore, for a strength for 5% Cysteine Hydrochloride Injection which will contain 34.6 mg/mL of Cysteine base,
`to provide 37.5 mg/kg/day for the first example given, administration 1.08 ml/kg/day will be needed instead of 0.75
`ml/kg/day. The following table compares the adjustment in admixture that is needed to provide the same amount of
`drug for each scenario.
`
`Dosage of Amino
`Acid
`
`Patient
`population
`
`Dosage of Cysteine
`
`2.5 g/kg/day
`3 g/kg/day
`
`Infant
`Infant
`Adult
`
`37.5 mg/kg/day
`45 mg/kg/day
`60 mg/100 mL of
`amino acid
`
`Amount of Cysteine
`Hydrochloride Injection
`Needed (7.25%)
`0.75 mL/kg/day
`0.9 mL/kg/day
`6 mL/500mL of amino
`acid
`
`Amount of Cysteine
`Hydrochloride Injection
`Needed (5%)
`1.09 mL/kg/day
`1.3 mL/kg/day
`8.7 mL/500 mL amino
`acid
`
`The proposed drug product will reduce the waste of unused drug based on the dosage recommendation in both infant
`and adult.
`
`There are no proposed changes in labeling with the exception of the obvious changes in strength and amount to be
`admixed sought in this petition. The uses, indications, warnings and directions for use will remain the same as that
`of the RLD. Draft labeling for the proposed product is included in Attachment 2, and the RLD's approved labeling is
`provided in Attachment 3.
`
`Therefore, the petitioner's request for the Commissioner to find that a change in strength (i.e., a change in total drug
`content) from 0.5 g to 0.346 g, for Cysteine Hydrochloride Injection should raise no questions of safety or
`effectiveness, and the Agency should approve the petition.
`
`Applicability of Pediatric Research Equity Act
`
`In September of 2007, Congress reauthorized the Pediatric Research Equity Act of 2003 (PREA) that amended the
`Federal Food, Drug, and Cosmetic Act to provide the Agency authority to require drug firms to study drugs in
`pediatric patients, if the Agency concludes that such study would provide beneficial health data for that patient
`population. The Act specifically requires that ANDAs submitted under an approved suitability petition under
`section 505(j)(2)(C) of the Act for changes in dosage form, route of administration, or new active ingredient in
`combination products are subject to the pediatric assessment requirements that PREA imposes. Since this petition is
`not seeking for a change in any of the changes listed and is limited to change in strength (total amount in a vial),
`requirement of PREA does not apply.
`
`C. Environmental Impact
`
`The petitioner claims a categorical exclusion under 21 CFR 25.31.
`
`D. Economic Impact
`
`The petitioner does not believe that this is applicable in this case, but will agree to provide such an analysis, if
`requested by the Agency.
`
`E. Certification
`
`The undersigned certifies that to the best knowledge and belief of the undersigned, this petition includes all
`information and views on which the petition relies, and that it includes representative data and information known to
`the petitioner, which are unfavorable to the petition.
`
`www.lachmanconsultants.com
`
`Eton Ex. 1092
`2 of 12
`
`

`

`LACHMAN CONSULTANT SERVICES, INC.
`Westbury, NY 11590
`
`Division of Dockets Management
`Food and Drug Administration
`May 8, 2018
`Page 3 of 3
`
`Respectfully submitted,
`Digitally signed by
`s.ahmed@lachmanconsultants.com
`Date: 2018.05.08 14:21:56 -04'00'
`Sharif Ahmed
`Principal Consultant
`
`Attachments:
`
`1. Approved Drug Products with Therapeutic Equivalence Evaluations, Electronic Orange Book
`listing, accessed 5/8/2018
`2. Draft insert labeling for proposed product
`3. Approved labeling for reference-listed drug, Cysteine Hydrochloride Injection 7.25%.
`
`www.lachmanconsultants.com
`
`Eton Ex. 1092
`3 of 12
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`

`

`Home > Drug Databases > Orange Book Home
`
`Orange Book: Approved Drug Products with Therapeutic Equivalence
`Evaluations
`
`f SHARE
`
`'tl 1WEET
`
`in UNKEOIN ® PIN IT II EMAIL Q PRINT
`
`Product Details for NDA 019523
`
`CYSTEINE HYDROCHLORIDE (CYSTEINE HYDROCHLORIDE)
`7.25% **Federal Register determination that product was not discontinued or withdrawn for safety or efficacy reasons.. Marketing Status: Discontinued
`
`Active Ingredient: CYSTEINE HYDROCHLORIDE
`Proprietary Name: CYSTEINE HYDROCHLORIDE
`Dosage Form; Route of Administration: INJECTABLE; INJECTION
`Strength: 7.25% .. Federal Register determination that produ ct was not discontinued or withdrawn for safety or efficacy reasons ..
`Reference Listed Drug: Yes
`Reference Standard: No
`TE Code:
`Application Number: N019523
`Product Number: 001
`Approval Date: Oct 22, 1986
`Applicant Holder Full Name: HOSPIRA INC
`Marketing Status: Discontinued
`_F'c.tt~llt a.n.~ E:J<C.Ilj~iyity ln.f()f111(1tic:>n.
`
`
`
`Eton Ex. 1092
`4 of 12
`
`

`

`5.0% Cysteine Hydrochloride Injection, USP (0.346 g Cysteine)
`
`DESCRIPTION
`
`5.0% Cysteine Hydrochloride Injection, USP (0.346 as the monohydrate), is a sterile,
`nonpyrogenic solution. Each 10 ml provides 0.346 g cysteine and 2.85 mEq of chloride in Water
`for Injection, USP. The pH range is 1.0 to 2.5. Cysteine is a sulfur-containing amino acid which
`is unstable when included in autoclaved solutions of amino acids. To avoid this problem,
`Cysteine Hydrochloride Injection is provided as an additive to use with amino acids solutions.
`The structural formula for cysteine hydrochloride is:
`
`CLINICAL PHARMACOLOGY
`
`
`
`In the adult, cysteine is synthesized from methionine via the trans-sulfuration pathway. However,
`in newborn infants maturation of the enzyme system needed to convert methionine to cysteine is
`not complete; therefore, cysteine is generally considered an essential amino acid in infants. In
`addition, adult and pediatric patients with severe liver disease may have an impairment of the
`enzymatic conversion of methionine to cysteine.
`
`INDICATIONS AND USAGE
`
`5.0% Cysteine Hydrochloride Injection, USP is indicated for use as an additive to amino acids
`solutions to meet nutritional requirements of newborn infants requiring total parenteral nutrition
`(TPN) and of adult and pediatric patients with severe liver disease who may have impaired
`enzymatic processes and require TPN. It can also be added to amino acids solutions to provide a
`more complete profile of amino acids tor protein synthesis.
`
`CONTRAINDICATIONS
`
`Due to the acidity of the solution, 5.0% Cysteine Hydrochloride Injection, USP should not be
`given by direct injection into a peripheral vein because phlebitis may result.
`
`WARNINGS AND PRECAUTIONS
`
`5.0% Cysteine Hydrochloride Injection, USP is a hypertonic solution and should be administered
`only as a component of an admixture of parenteral nutrients. It is only to be administered
`intravenously.
`
`Eton Ex. 1092
`5 of 12
`
`

`

`Pregnancy Category C.
`
`Animal reproduction studies have not been conducted with 5.0% Cysteine Hydrochloride
`Injection, USP. It is also not known whether 5.0% Cysteine Hydrochloride Injection, USP can
`cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
`5.0% Cysteine Hydrochloride Injection, USP should be given to a pregnant woman only if
`clearly needed.
`
`ADVERSE REACTIONS
`
`No adverse reactions to Cysteine Hydrochloride Injection have been reported at the
`recommended dosage levels.
`
`DOSAGE AND ADMINISTRATION
`
`For addition to amino acids solutions intended for use in newborn infants, it is recommended that
`5.0% Cysteine Hydrochloride Injection, USP be added to the amino acids solution to provide
`cysteine at approximately 1.5% of the total amino acids being supplied. Hence, an infant
`receiving amino acids solutions at 2.5 g/kg/day should be provided 37.5 mg/kg/day of cysteine or
`1.00 ml/kg/day of 5.0% Cysteine Hydrochloride Injection, USP. An infant receiving 3.0
`g/kg/day of amino acids should be provided 1.3 ml/kg/day of 5.0% Cysteine Hydrochloride
`Injection, USP.
`
`For addition to amino acids solutions that are intended for use in adults, a dosage of 5 mg of
`cysteine per gram of amino acids can be used. For example: 8.7 ml of 5.0% Cysteine
`Hydrochloride Injection, USP added to 500 ml of Novamine™ 11.4% Amino Acids Injection
`will provide a final concentration of 60 mg cysteine/100 ml of amino acids solution.
`
`These amino acids admixtures should then be aseptically diluted with appropriate caloric
`substrates calculated to supply the patient with adequate energy. The admixture should be
`refrigerated until ready for use and used within 24 hours of the time of mixing.
`
`Parenteral drug products should be inspected visually for par1iculate matter and discoloration
`prior to administration, whenever solution and container permit.
`
`HOW SUPPLIED
`
`5.0% Cysteine Hydrochloride Injection, USP (0.346 g cysteine) is supplied in a 10 mL vial.
`
`Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
`recommended that the product be stored at room temperature (25°C); however, brief exposure up
`to 40°C does not adversely affect the product. Solution that has been frozen must not be used.
`
`NDC: To be assigned
`
`May 2018
`
`Eton Ex. 1092
`6 of 12
`
`

`

`Rev. 10/7/86, ~o~ 19-523
`7 .25'1- cystei ne \\C1
`
`SYR!MGE LABEL
`
`4.a.-1
`
`10 Ml..
`
`NOC ()80i-047'l-i0
`
`7.25% CVSTElNE HYOROCHLORlOE
`lNJECTlON, USP
`\0.5 G CYSTEINE)
`S1NG\..E DOSE CONTAINER
`STEFl\lE - NONP'IAOOEN\C
`FQR \NTRAVENOUS uSE AfTEP. OllUi\ON
`SE.E PACK.AGE. INSERT
`CAU"TlON US FEDERAL \.faN PAOHlBlTS OlSPENSJNG W)THOU1
`GODE
`473.10
`
`PRESCRIPTION
`
`OATI,D-0
`
`DiSiR!SUTED SY
`Kabl'Vitrum, \oc. -;;.t;
`~ c>,9'5QtU~
`
`EXP OAfE
`
`:", ..
`
`•
`
`Eton Ex. 1092
`7 of 12
`
`

`

`Rev. 10/7/86, NDA 19-523
`7.25% Cysteine HCl
`
`,:f-',, -
`-- .
`
`·1ng
`L"
`~ae.
`:
`
`NDANo: I/ ,4,~~ /(
`Revtewed by: + Pl /j:r=,e~
`
`4.a.-2
`
`7· f- f
`j sl 2 ':/ rr.
`
`UNIT CARTON
`
`___ ,
`
`NDC 0601-0473-10
`
`7.25% Cysteine
`Hydrochloride
`Injection, USP
`(0.5 g Cysteine)
`
`For Intravenous Use
`After DIiution
`
`Sterile - Nonpyrogenic
`Single Dose Container
`
`CAUTION: U.S. Federal
`law prohibits dispensing
`without prescription.
`
`Code
`473-10
`
`10 ml
`
`Distributed by
`I &2'
`KabiVrtrum, nc. OG
`Alameda, CA !U.501 USA
`
`APPROVFn
`
`Eton Ex. 1092
`8 of 12
`
`

`

`Rev, 10/7/86, NDA 19-523
`7.2si Cysteine HCl
`
`4.c.-1
`
`PACKAGE INSERT
`
`I
`
`•
`
`•
`747310-0
`{Mar 1986)
`7 .25% Cystelne
`Hydrochloride
`Injection, USP,
`In 10 ml Additive Syringe
`
`DESCRIPTION
`7.25% Cysteine Hydrochloride
`Injection, USP (0.725 gas the
`monohydrate), is a sterile, non(cid:173)
`pyrogenic sotution. Each 10 ml pre;
`vides 0.5 g cysteine and 4.13 mEq of
`chloride in Water for Injection, USP.
`The pH range is 1.0 to 2.5. Cysteine is
`a sulfur-containing amino acid which is
`unstable when included in autoclaved
`solutions of amino acids. To avoid this
`problem, Cysteine Hydrochloride Injec(cid:173)
`tion is provided as an additive to use
`with amino acids solutions. The struc(cid:173)
`tural formula for cysteine hydrochloride
`is:
`
`H
`
`'
`HSCH2 - C - COCH • HCI • H20
`
`NH,
`
`CLINICAL PHARMACOLOGY
`In the adult, cysteine is synthesized
`from methionine via the trans(cid:173)
`sulfuration pathway. However, in
`newborn infants maturation of the en(cid:173)
`zyme system needed to convert
`methionine to cysteine is not complete;
`therefore, cysteine is generally con(cid:173)
`sidered an essential amino acid in in(cid:173)
`fants. In addition, adult and
`pediatric patients with severe liver
`disease may have an impairment of
`the enzymatic conversion of
`methionine to cysteine.
`
`APPROVED
`
`"' 2
`
`•
`
`Eton Ex. 1092
`9 of 12
`
`

`

`Rev. 10/7/86, NOA 19-523
`7.25% Cysteine HCl
`
`4.c.-1
`
`PACKAGE INSERT
`
`INDICATIONS AND USAGE
`7.25% Cysteine Hydrochloride
`Injection, USP is indicated for use as
`an additive to amino acids solutions to
`meet nutritional requirements of
`newborn infants requiring total
`parenteral nutrition (TPN) and of adult
`and pediatric patients with severe liver
`disease who may have impaired enzy·
`matic processes and require TPN. It
`can also be added to amino acids
`solutions to provide a more complete
`profile of amino acids tor protein
`synthesis.
`
`CONTRAINDICATIONS
`Due to the acidity of the solution,
`7.25% Cysteine Hydrochloride
`Injection, USP should not be given by
`direct injection into a peripheral vein
`because phlebitis may result.
`
`WARNINGS AND PRECAUTIONS
`7.25% Cysteine Hydrochloride
`Injection, USP is a hypenonic solution
`and should be administered only as a
`component of an admixture of
`parenteral nutrients. It is only to be
`administered intravenously.
`Pregnancy category C
`Animal reproduction studies have not
`been conducted with 7.25% Cysteine
`Hydrochloride Injection, USP. It is also
`not known whether 7.25% Cysteine
`Hydrochloride Injection, USP can
`cause fetal harm when administered to
`a pregnant woman or can affect
`reproduction capacity. 7.25% Cysteine
`Hydrochloride Injection, USP should
`be given to a pregnant woman only if
`clearly needed.
`
`ADVERSE REACTIONS
`No adverse reactions to Cysteine
`Hydrochloride Injection have been
`reponed at the recommended dosage
`levels.
`
`DOSAGE ANO ADIIINISTRA TION
`For addition to amino acids solutions
`intended for use in newborn infants, it
`is recommended that 7 .25% Cysteine
`Hydrochloride Injection, USP be added
`to the amino acids solution to provide
`cysteine at approximately 1.5% of the
`total amino acids being supplied.
`Hence, an infant receiving amino acids
`solutions at 2.5 g/kg/day should be
`provided 37.5 mg/kg/day of cysteine
`or 0.75 ml/kg/day of 7.25% Cysteine
`Hydrochloride Injection, USP. An in(cid:173)
`fant receiving 3.0 g/kg/day of amino
`acids should be provided
`0.9 ml/kg/day of 7.25% Cysteine
`Hydrochloride Injection, USP.
`For addition to amino acids solutions
`that are intended for use in adults, a
`dosage of 5 mg of cysteine per gram
`of amino acids can be used. For
`example: 6 ml of 7.25% Cysteine
`Hydrochloride Injection, USP added to
`500 ml of Novamine"' 11.4% Amino
`Acids Injection will provide a final con(cid:173)
`centration of 60 mg cysteinenoo ml
`of amino acids solution.
`These amino acids admixtures
`should then be aseptically diluted
`with appropriate caloric substrates
`calculated to supply the patient with
`adequate energy. The admixture
`should be refrigerated until ready for
`use and used within 24 hours of the
`time of mixing_
`Parenteral drug products should be
`inspected visually for par1iculate mat(cid:173)
`ter and discoloration prior to adminis(cid:173)
`tration, whenever solution and con(cid:173)
`tainer permit.
`
`HOW SUPPLIED
`7.25% Cyste1ne Hydrochloride
`Injection, USP (0.5 g cysteine) is
`supplied in a 10 ml additive syringe.
`Exposure of pharmaceutical products
`to heat should be minimized. Avoid
`
`2
`
`3
`
`APPROVED
`
`Eton Ex. 1092
`10 of 12
`
`

`

`Rev. 10/7/86, NDA 19-523
`7.2si Cysteine HCl
`
`4.c.-1
`
`PACKAGE INSERT
`
`excessive heat. It is recommended
`that the product be stored at room
`temperature (25°C); however, brief
`exposure up to 40°C does not
`adversely affect the product. Solution
`that has been frozen must not be
`used.
`
`NOC 0601-0473-10
`(Mar 1986)
`
`Olltributecl by
`
`KabtVttrum, Inc. ~@:,
`
`Alameda, CA 94601 USA
`
`APPROVED
`
`4
`
`•
`
`Eton Ex. 1092
`11 of 12
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
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`
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`Public Health Service
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`May 9, 2018
`
`Sharif Ahmed
`Lachman Consultant Services, Inc.
`1600 Stewart Avenue
`Westbury, NY 11590
`
`Sent via email to: s.ahmed@lachmanconsultants.com
`
`Dear Petitioner:
`
`
`Your petition to the Food and Drug Administration requesting that the Commissioner
`declare that Cysteine Hydrochloride Injection 5% containing 34.6 mg/mL of Cysteine base
`are suitable for consideration in an abbreviated new drug application was received by this
`office on 5/8/2018.
`
`It was assigned docket number FDA-2018-P-1808. Please refer to this docket number in
`future correspondence on this subject with the Agency.
`
`
`Please note that the acceptance of the petition for filing is a procedural matter in that it in no
`way reflects an agency decision on the substantive merits of the petition.
`
`Sincerely,
`
`
`
`Dynna Bigby
`Supervisory Administrative Proceedings Specialist
`Division of Dockets Management
`FDA/Office of the Executive Secretariat (OES)
`
`
`
`
`
`Eton Ex. 1092
`12 of 12
`
`