CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202231Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`
`
`NDA 202231
`
` Levothyroxine Sodium
` for Injection
`
`Summary of the Basis for the Recommended Action
` from Chemistry, Manufacturing, and Controls
`
`
`
`Applicant: APP Pharmaceuticals, LLC.
`1501 E. Woodfield Rd.
`Suite 300
`E. Schaumburg, IL 60173
`
`Indication: Levothyroxine sodium for injection is indicated to treat
` myxedema coma.
`
`
`
`
`Presentation: Levothyroxine sodium for injection is packaged in single-use amber glass
`
`
`vials closed with a 20 mm gray
` rubber lyophilization stopper
`
`
`and capped with an aluminum crimped flip cap seal available in three
`
`
`dosage strengths: 100 mcg/vial, 200 mcg/vial and 500 mcg/vial.
`
`Establishments Evaluation Report (EER) Status:
`
`Consults:
`
`
`
`
`Acceptable
`
`
`
`EA –
`
`
`Statistics –
`Methods Validation –
`Biopharm –
`
`
`Microbiology –
`
`Pharm Toxicology –
`
`Acceptable
`N/A
`Not requested
`N/A
`Acceptable
`N/A
`
`
`
`
`
`Original Submission:
`
`
`Re-submissions:
`
`Post-Approval CMC Agreements:
`
`Drug Substance
`Levothyroxine sodium (C15H10I4NNaO4; MW = 798.85) is a light yellow to buff-colored,
`odorless, hygroscopic powder. It is stable in dry air but may assume a slight pink color
`upon exposure to light. It is very slightly soluble in water and slightly soluble in alcohol.
`Levothyroxine sodium is manufactured in the optically active L-form and has the
`following structure:
`
`August 30, 2010
`N/A
`None at this time.
`
`
`
`Reference ID: 2940300
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202-23 1
`
`Summary Basis of Recommended Action — CMC
`
`P. 2
`
`unlllZ
`
`CHz-iJH—COONa+
`
`H
`
`The drug substance specifications meet all requirements of the current USP monograph
`for levothyroxine sodium (updated Aug 1, 2008) with the addition of description,
`residual solvents, bioburden and bacterial endotoxins. All impurities and their limits are
`the same as listed in the USP monograph.
`
`Information for the drug substance is provided in th— DMF-
`and'1s incorporated by reference herein. A copy of the letter of authorization to reference
`DIVIF- has been provided. The DMF was reviewed by]. Leginus on Feb 11,2011 and
`
`found.tobeadfite.Theretestgodforthedruisubstancerssetat—
`
`Drug substancers satisfactory
`
`
`
`Drug product
`The drug product, levothyroxine sodium for injection, is a sterile, lyophilized powder
`consisting of the active ingredient, synthetic levothyroxine sodium, and the excipinets
`dibasic sodium phosphate, heptahydrate, USP; mannitol, USP; and sodium hydroxide,
`NF. Levothyroxine sodium for injection is packaged in single—use amber glass vials
`available111 three dosage strengths: 100 mcg/vial, 200 mc vial and 500 mc
`vial.
`
`
`
`'
`
`'cations include description, reconstitution time, visual
`The proposed release 3
`uniformity of dosage units, instrumental color, identity
`inspection, pH,
`(I-lPLC), assay (I-IPLC), individual and total impurities (HPLC),—
`contarner/closure integrity, particulate matter, sterility and bacterial endotoxin. AH
`noncompendial regulatory methods have been validated.
`
`
`
`vials are used as the primary packaging material, which have been shown to adequately
`protect the lyophilized drug product from degradation due to light.
`
`The applicant has provided only 6 months of real time (25°C/60% RH) and accelerated
`(40°C/75% RH) stability data for the three strengths of the drug product in stoppered
`and sealed vials. Results from stability studies show that the drug product remains
`
`Reference ID: 2940300
`
`

`

`NDA 202-231
`
`Summary Basis of Recommended Action – CMC
`
`P. 3
`
`stable through 6 months under both conditions. In-use results show that drug product
`reconstituted with the recommended reconstitution diluent (0.9% sodium chloride
`injection, USP) remains stable for up to 4 hours at room temperature following
`dissolution, which supports the drug product label statement of “Use immediately after
`reconstitution”. Based on these data, and following the recommendations outlined in
`ICH Q1E Evaluation of Stability Data, a shelf-life of 12 months is granted for
`levothyroxine sodium for injection when stored at controlled room temperature (20°C –
`25°C).
`Drug product is satisfactory
`
`Overall Conclusion:
`The NDA is recommended for Approval from the standpoint of chemistry,
`manufacturing and controls.
`
`
`
`Ali Al-Hakim, Ph.D.
`Branch Chief, Division III
`ONDQA/CDRR/FDA
`
`
`
`
`
`
`
`Reference ID: 2940300
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALI H AL HAKIM
`04/29/2011
`
`Reference ID: 2940300
`
`

`

`
`
`NDA 202231
`
`Levothyroxine Sodium
`
`for Injection
`
`APP Pharmaceuticals, LLC
`
`Joseph Leginus, PhD
`Division of Pre—Marketing Assessment III, Branch VII, ONDQA
`
`For the Division of
`
`Metabolism and Endocrinology Products
`
`CHEMISTRY REVIEW #2
`
`Reference ID: 29401 57
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`1. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 7
`
`II. Summary of Chemistry Assessments......................................................................................... 7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 7
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 9
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative ......................................................................................................................... 10
`
`A. Reviewer’s Signature:
`
`in DARRTS ........................................................................................... 10
`
`B. Endorsement Block:
`
`in DARRTS ............................................................................................... 10
`
`C. CC Block:
`
`in DARRTS ............................................................................................................ 10
`
`Chemistry Assessment ........................................................................................... l 1
`
`Reference ID: 29401 57
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 202231
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 29—Apr—2011
`
`4. REVIEWER: Joseph Leginus, PhD
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original NDA
`
`Document Date
`
`30-Aug-2010
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissiong s! Reviewed
`NDA Amendment
`
`Document Date
`18-Feb-2100
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`APP Pharmaceuticals, LLC
`
`Address:
`
`1501 E. Woodfield Rd. Suite 300 E, Schaumburg, IL 60173
`
`Representative:
`
`Telephone:
`
`Brent Yurschak, Regulatory Scientist
`
`847—330-3896
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: N/A
`b) Non-Proprietary Name a}SAN): Levothyroxine Sodium for Injection
`c) Code Name/# (ONDC only): CAS No.: 55-03-8
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 3 (New Dosage Form)
`
`0 Submission Priority: Standard
`
`Reference ID: 29401 57
`
`Page 3 of 15
`
`

`

`
`
`Chemistry Review Data Sheet
`
`9. LEGAL BASIS FOR SUBMISSION: This NDA is submitted as a 505(b)(2)
`application.
`
`10. PHARMACOL. CATEGORY:
`
`Replacement therapy for reduced or absent thyroid fimction of any etiology.
`
`l l. DOSAGE FORM: Lyophilized Powder for Injection
`
`12. STRENGTH/POTENCY: 100, 200 and 500 meg/vial
`
`13. ROUTE OF ADMINISTRATION: Intravenous (IV)
`
`mo
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name: L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-, monosodium
`salt
`
`Structural Formula:
`
`-IIIIIIZ
`CHz-i—COONa
`
`H
`
`Molecular Formula: C15HloI4NNaO4
`
`Molecular Weight: 798.85 (sodium salt)
`
`Reference ID: 29401 57
`
`Page 4 of 15
`
`

`

`
`
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUNIENTS:
`
`(IN
`
`.
`.
`Levothyroxme Sodium
`
`Drug Substance --11 Feb 2011
`
`I
`
`.
`Rev1ewed by
`
`J. Leginus
`
`Reviewed by
`
`Reviewed by
`
`
`
`II
`
`HI
`
`III
`
`111
`
`V
`
`Adequate
`
`19-Mar-2010
`
`Re‘f‘ewed by
`S. Znnmerman
`
`Adequate
`
`12-Aug-2010
`
`Reviewed by
`S. Donald
`
`lAction codes for DNIF Table:
`l — DNIF Reviewed.
`
`Other codes indicate why the DIvIF was not reviewed. as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under “Comments")
`
`2 Adequate. Inadequate. or N/A (There is enough data in the application. therefore the DMF did not need to
`be reviewed)
`
`B. Other Documents:
`
`
`DOCUMENT APPLICATION NUMBER
`DESCRIPTION
`
`101,385
`
`Levoth oxine Sodium for In'ection
`
`18. STATUS:
`
`ONDC:
`CONSULTS/ CMC
`
`RELATED REVIEWS
`
`RECOMMENDATION -w Acceptable. An Overall
`
`Compliance recommendation
`ofAcceptable has been
`.rovided.
`
`25-Jan-2011
`
`N/A
`
`Reference ID: 29401 57
`
`Page 5 0f 15
`
`

`

`
`
`Not applicable. Impurity and
`degrath limits are below
`ICH qualification thresholds
`and/or comply with
`com -ndial limits.
`
`Validation may be requested
`of FDA labs alter test
`methods are finalized.
`
`The application is
`recommended for approval
`from microbiology product
`uali
`stand int.
`
`.
`.
`Mcroblology
`
`26-Apr-2011
`
`Robert Mello
`
`_———
`
`19. ORDER OF REVIEW: N/A
`
`Reference ID: 29401 57
`
`Page 6 of 15
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 202231
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`NDA 202231 is recommended for Approval from the standpoint of chemistry,
`manufacturing and controls.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`Not applicable.
`
`11.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`DRUG SUBSTANCE
`
`Levothyroxine sodilnn (C 15H1014NNaO4; MW = 798.85) is a light yellow to buff—colored,
`odorless, hygroscopic powder. It is stable in dry air but may assume a slight pink color
`upon exposure to light. It is very slightly soluble in water and slightly soluble in alcohol.
`Levothyroxine sodium is manufactured in the optically active L-form and has the
`following structure:
`
`mgbio@CHz-iC—cooNa
`
`IIIIIIZ
`
`The drug substance specifications meet all requirements of the current USP monograph
`for levothyroxine sodium (updated Aug 1, 2008) with the addition of description, residual
`solvents, bioburden and bacterial endotoxins. All impurities and their limits are the same
`as listed in the USP monograph.
`
`(m4) DMF (m4)
`Information for the drug substance is provided in the
`andIS incorporated by reference herein. A copy of the letter of authorization to reference
`DMF
`(me has been provided. The DMF was reviewed by J. Leginus on Feb 112011
`and found to be adequate. The retest period for the drug substbagce1s set at
`I
`(we)
`
`Reference ID: 29401 57
`
`Page 7 of 15
`
`

`

`aha-n
`m: i
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`ans-n
`E m i
`
`DRUG PRODUCT
`
`The drug product, levothyroxine sodium for injection, is a sterile, lyophilized powder
`consisting of the active ingredient, synthetic levothyroxine sodium, and the excipients
`dibasic sodium phosphate, heptahydrate, USP; mannitol, USP; and sodium hydroxide,
`NF. Levothyroxine sodium for injection is packaged in single-use amber glass vials
`available in three dosage strengths: 100 meg/vial, 200 mcg/vial and 500 mcg/vial.
`
` The manufacture and lyophilization are conducted at APP Pharmaceuticals,
`
`Me ose Par , IL.
`
`The proposed release s
`inspection, pH
`
`ifications include description, reconstitution time, visual
`uniformity of dosage units, instrumental color, identity
`
`(HPLC), assay (HPLC), individual and total impurities (HPLC),H
`
`container/closure integrity, particulate matter, sterility and bacten en otoxm.
`compendial regulatory methods have been validated.
`
`non-
`
`Also, amber glass vials
`are used as the primary packaging material, which have been shown to adequately protect
`the lyophilized drug product from degradation due to light.
`
`The drug product is ackaged in a 20 mm neck, USP Type I amber glass vial closed with
`a 20 mm gra
`rubber lyophilization stopper and capped with an aluminum
`crimped flipcap seal. The size of the glass vial will vary depending on the dose. A 6.5 mL
`vial is used for the 100 mcg dose and 10 mL vials are used for both the 200 mcg and 500
`mcg doses. The storage condition for the drug product is controlled room temperature
`(20° - 25°C).
`
`The applicant has provided only 6 months ofreal time (25°C/60% RH) and accelerated
`(40°C/75% RH) stability data for the three strengths of the drug product in stoppered and
`sealed vials. Results from stability studies show that the drug product remains stable
`through 6 months under both conditions. In-use results show that drug product
`reconstituted with the recommended reconstitution diluent (0.9% sodium chloride
`injection, USP)l remains stable for up to 4 hours at room temperature following
`dissolution, which supports the drug product label statement of “Use immediately after
`reconstitution”. Based on these data, and following the recommendations outlined in ICH
`QlE Evaluation of Stability Data, a shelf-life of 12 months is granted for levothyroxine
`sodium for injection when stored at controlled room temperature (20°C — 25°C). -
`
`——
`
`Reference ID: 2940157
`
`Page 8 of 15
`
`

`

` CHEMISTRY REVIEW
`
`
`
`Executive Summary Section
`
`
` a 12 month expiry is granted for the
`
`B. Description of How the Drug Product is Intended to be Used
`
`(but)
`Levothyroxine sodium for injection is indicated to treat
`myxedema coma. Myxedema coma represents the extreme expression of severe
`hypothyroidism and is a life-threatening emergency characterized by poor circulation and
`hypometabolism. It may result in unpredictable absorption of levothyroxine sodium from
`the gastrointestinal tract, therefore, oral thyroid hormone drug products, such as the
`approved Synthroid® (NDA 21-402; Abbott), are not recommended to treat this
`condition. Thyroid hormone products formulated for intravenous administration should
`be administered.
`
`The applicant states that pharmacokinetic and clinical data support an initial loading dose
`of levothyroxine between 300 mcg to 500 mcg followed by daily maintenance doses
`between 50 mcg and 100 mcg until the patient can tolerate oral therapy. As a result, 3
`dosage strengths of levothyroxine sodium for injection have been manufactured: 100
`meg/vial, 200 mcg/vial and 500 meg/vial. Each dosage strength requires reconstitution
`using 5 mL of 0.9% sodium chloride injection, USP (not provided) immediately prior to
`intravenous administration.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`All items in the List of Deficiencies fiom Chemistry Review #1 have been satisfactorily
`addressed in the 18-Feb-2011 amendment to the original NDA. See Chemistry
`Assessment section below for details.
`
`Acceptable cGMP recommendations have been received from the Office of Compliance
`for all manufacturing and testing facilities. An Overall Compliance recommendation of
`Acceptable was provided on 25-Jan-2011.
`
`A recommendation for approval was received from the microbiology product quality
`standpoint.
`
`The applicant filed the NDA as a 505(b)(2) application for a new dosage form of
`levothyroxine sodium. The applicant’s product has been marketed in the US. as an
`unapproved drug. The FDA recently categorized Levothyroxine Sodium for Injection a
`“Marketed Unapproved Drug,” thus requiring submission of an NDA and FDA approval
`in order to keep the product on the market. This was communicated to the applicant in a
`Warning Letter issued by the FDA Chicago District on December 18, 2006. A pre-IND
`meeting was held with the Agency on March 18, 2008.
`
`Reference ID: 2940157
`
`Page 9 of 15
`
`

`

`
`
`Executive Summary Section
`
`The drug substance (levothyroxine sodium) will be manufactured for commercial use by
`as with most of the CMC parameters provided in
`no DMF No. an A copy of the letter of authorization to reference
`the
`DMF an has been provided. The drug substance specifications meet all requirements of
`the current USP monograph for levothyroxine sodium.
`
`The drug product, levothyroxine sodium for injection, is manufactured by APP
`Pharmaceuticals, Melrose Park, IL, as a sterile, lyophilized powder comprised of
`levothyroxine sodium, and the compendial excipients dibasic sodium phosphate,
`heptahydrate, mannitol and sodium hydroxide.
`
`Levothyroxine sodium for injection was found to be photosensitive, therefore, the
`primary container closure is an amber glass vial, which provides adequate protection
`from light. A label statement indicates to protect the drug product from light.
`
`No additional impurities have been imparted to the drug product during its manufacture
`or found during stability testing.
`
`Based on the limited stability data (6 months), a shelf life of 12 months at controlled
`room temperature (20°C — 25°C) is granted for levothyroxine sodium for injection.
`
`III. Administrative
`
`A. Reviewer’s Signature:
`B. Endorsement Block:
`C. CC Block:
`
`in DARRTS
`in DARRTS
`in DARRTS
`
`
`
`Reference ID: 29401 57
`
`Page 10 of 15
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOSEPH M LEGINUS
`04/29/2011
`
`ALI H AL HAKIM
`04/29/2011
`
`Reference ID: 2940157
`
`

`

`
`
`NDA 202231
`
`Levothyroxine Sodium
`
`for Injection
`
`APP Pharmaceuticals, LLC
`
`Joseph Leginus, PhD
`Division of Pre—Marketing Assessment III, Branch VII, ONDQA
`
`For the Division of
`
`Metabolism and Endocrinology Products
`
`CHEMISTRY REVIEW #1
`
`Reference ID: 2895223
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`1. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps, if Approvable ................................................................................................... 7
`
`II. Summary of Chemistry Assessments......................................................................................... 7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 7
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 9
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative ......................................................................................................................... 10
`
`A. Reviewer’s Signature: in DFS ........................................................................................................ 10
`
`B. Endorsement Block: in DFS ........................................................................................................... 10
`
`C. CC Block: in DFS ........................................................................................................................... 10
`
`Chemistry Assessment ........................................................................................... l 1
`
`I. Review of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body of Data .......... 11
`
`S DRUG SUBSTANCE .................................................................................................................... 11
`
`P DRUG PRODUCT ........................................................................................................................ 21
`
`A APPENDICES ............................................................................................................................... 54
`
`R REGIONAL INFORMATION ...................................................................................................... 54
`
`II. Review of Common Technical Document—Quality (Ctd—Q) Module 1 ................................... 55
`
`A. Labeling & Package Insert ............................................................................................................. 55
`
`B. Environmental Assessment or Claim of Categorical Exclusion .................................................... 62
`
`List of Deficiencies To Be Communicated .......................................................................................... 63
`
`Reference ID: 2895223
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 202231
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 24—Jan—2011
`
`4. REVIEWER: Joseph Leginus, PhD
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`N/A
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissiong s! Reviewed
`Original NDA
`
`Document Date
`30-Aug-2010
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`APP Pharmaceuticals, LLC
`
`Address:
`
`1501 E. Woodfield Rd. Suite 300 E, Schaumburg, IL 60173
`
`Representative:
`
`Telephone:
`
`Brent Yurschak, Regulatory Scientist
`
`847—330-3896
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: N/A
`b) Non-Proprietary Name a}SAN): Levothyroxine Sodium for Injection
`c) Code Name/# (ONDC only): CAS No.: 55-03-8
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 7 (Drug Already Marketed but Without an Approved NDA)
`
`0 Submission Priority: Standard
`
`Reference ID: 2895223
`
`Page 3 0f 63
`
`

`

`
`
`Chemistry Review Data Sheet
`
`9. LEGAL BASIS FOR SUBMISSION: This NDA is submitted as a 505(b)(2)
`application.
`
`10. PHARMACOL. CATEGORY:
`
`Replacement therapy for reduced or absent thyroid fimction of any etiology.
`
`l l. DOSAGE FORM: Lyophilized Powder for Injection
`
`12. STRENGTH/POTENCY: 100, 200 and 500 meg/vial
`
`13. ROUTE OF ADMINISTRATION: Intravenous (IV)
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM ):
`
`
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name: L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-, monosodium
`salt
`
`Structural Formula:
`
`IIIIIIZ
`CHz-i—COONa
`
`H
`
`Molecular Formula: C15HloI4NNaO4
`
`Molecular Weight: 798.85 (sodium salt)
`
`Reference ID: 2895223
`
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`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DMFs:
`
`
`
`Levothyroxine Sodium
`Drug Substance
`
`(bx
`
`.
`Defic1ent
`
`Adequate
`
`05 Oct 2010
`
`Reviewed by
`D. Klein
`,-
`15-Dec-2005 Re‘fggby
`Reviewed by
`
`Adequate
`
`1 9-Mar-201 0
`
`Rev'lewed by
`S. Zimmerman
`
`-- 12-Aug-2010
`
`Reviewed by
`
`8-Donald
`
`lAction codes for DNIF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed. as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under “Comments")
`
`2Adequate. Inadequate. or N/A (There is enough data in the application. therefore the DMF did not need to
`be reviewed)
`
`B. Other Documents:
`
`
`DOCUMENT APPLICATION NUMBER
`DESCRIPTION
`
`101,385
`
`Levoth oxine Sodium for In'ection
`
`18. STATUS:
`
`ONDC:
`CONSULTS/ CMC
`RELATED REVIEWS
`
`RECOMIVIENDATION
`
`DATE
`
`REVIEWER
`
`—-——— Not applicable. Impurity and
`
`PhamllTox
`
`degrath limits are below
`ICH ualification thresholds
`
`Reference ID: 2895223
`
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`
`
`Chemistry Review Data Sheet
`
`and/or comply with
`com» ndial limits.
`
`Methods Validation
`
`Validation may be requested
`of FDA labs afler test
`methods are finalized.
`
`_———
`
`Microbiolo
`
`-—— Robert Mello
`
`14-Jan-2011
`
`l9. ORDER OF REVIEW: N/A
`
`Reference ID: 2895223
`
`Page 6 0f 63
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 22-382
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is approvable from the standpoint of chemistry, manufacturing
`and controls pending a) satisfactory responses to the deficiencies delineated in the
`List of Deficiencies and Information Request (in the CMC Review #1 for NDA
`202231), and b) an adequate response to the Master File Deficiency detailedm S.
`Khushboo’3 letter (10/12/231419) to the drug substance manufacturer,
`on»
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`Not applicable.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`DRUG SUBSTANCE
`
`Levothyroxine sodium (C15HloI4NNaO4; MW = 798.85) is a light yellow to buff-colored,
`odorless, hygroscopic powder. It is stable in dry air but may assume a slight pink color
`upon exposure to light. It is very slightly soluble in water and slightly soluble in alcohol.
`Levothyroxine sodium is manufactured in the optically active L—form and has the
`following structure:
`
`Hoflo«Q—CHz—jzC—cooNa
`
`-uIIIZ
`
`The drug substance specifications meet all requirements of the current USP monograph
`for levothyroxine sodium (updated Aug 1, 2008) with the addition of description, residual
`solvents, bioburden and bacterial endotoxins. All impurities and their limits are the same
`as listed in the USP monograph.
`
`(m4)
`Information for the drug substance is provided in the
`and is incorporated by reference herein. A copy of the letter of authorization to reference
`
`Reference ID: 2895223
`
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`

`

`gnu-n
`m: .
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`—.A'h
`_ t L._.
`
`.
`
`has been provided. The DMF was reviewed by K. Fumkranz on Apr 29, 2008
`oun to be adequate, however, a Master File Deficienc letter was sent (10/12/2010)
`
`an
`
`to thedrug substancemanufacturer,” indicatingthat
`
`ual Report did
`eport an
`their 3/3/2010 Amendment, 3/4/200
`not have the required CMC data for the most recently manufactured drug substance
`batches. No response from manufacturer to this letter has been received at this time. The
`retest
`'od for the
`substance
`
`DRUG PRODUCT
`
`The drug product, levothyroxine sodium for injection, is a sterile, lyophilized powder
`consisting of the active ingredient, synthetic levothyroxine sodium, and the excipients
`dibasic sodium phosphate, heptahydrate, USP; mannitol, USP; and sodium hydroxide,
`NF. Levothyroxine sodium for injection is packaged in single-use amber glass vials
`available in three dosage strengths: 100 mcg/vial, 200 mcg/vial and 500 meg/vial.
`
` The manufacture and lyophilization are conducted at APP Pharmaceuticals,
`
`Melrose Park, IL.
`
`ifications include description, reconstitution time, visual
`The proposed release s
`uniformity of dosage units, instrumental color, identity
`inspection, pH
`(HPLC), assay (HPLC), individual and total impurities (I-IPLC)
`container/closure integrity, particulate matter, sterility and bacterial endotoxin. All non-
`compendial regulatory methods have been validated.
`
`Also, amber glass vials
`are used as the primary packaging material, which have been shown to adequately protect
`the lyophilized drug product from degradation due to light.
`
`The drug product is acka ed in a 20 mm neck, USP Type I amber glass vial closed with
`
`a 20 mm grayimbber lyophilization stopper and capped with an aluminum
`
`crimped flipcap seal. The size of the glass vial will vary depending on the dose. A 6.5 mL
`vial is used for the 100 mcg dose and 10 mL vials are used for both the 200 mcg and 500
`mcg doses. The storage condition for the drug product is controlled room temperature
`(20° - 25°C).
`
`The applicant has provided only 6 months ofreal time (25°C/60% RH) and accelerated
`(40°C/75% RH) stability data for the three strengths of the drug product in stoppered and
`sealed vials. Results from stability studies show that the drug product remains stable
`
`Reference ID: 2895223
`
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`

`
`
`Executive Summary Section
`
`through 6 months under both conditions. In-use results show that drug product
`reconstituted with either of the two recommended reconstitution diluents remains stable
`
`for up to 4 hours at room temperature following dissolution, which supports the drug
`product label statement of “Use immediately after reconstitution”. Based on these data,
`and following the recommendations outlined in ICH QEl Evaluation of Stability Data, a
`shelf—life of 12 months is granted for levothyroxine sodium for injection when stored at
`controlled room temperature (20°C — 25°C).
`(mo
`
`a 12 month expiry is granted for the drug product at this time.
`
`B. Description of How the Drug Product is Intended to be Used
`
`(m4)
`Levothyroxine sodium for injection is indicated to treat
`myxedema coma. Myxedema coma represents the extreme expression of severe
`hypothyroidism and is a life—threatening emergency characterized by poor circulation and
`hypometabolism. It may result in unpredictable absorption of levothyroxine sodium from
`the gastrointestinal tract, therefore, oral thyroid hormone drug products, such as the
`approved Synthroid® (NDA 21-402; Abbott), are not recommended to treat this
`condition. Thyroid hormone products formulated for intravenous administration should
`be administered.
`
`The applicants states that pharmacokinetic and clinical data support an initial loading
`dose of levothyroxine between 300 pg to 500 pg followed by daily maintenance doses
`between 50 pg and 100 pg until the patient can tolerate oral therapy. As a result, 3 dosage
`strengths of levothyroxine sodium for injection have been manufactured: 100 mcg/vial,
`200 mcg/vial and 500 meg/vial. Each dosage strength requires reconstitution using 5 mL
`of either 0.9% sodium chloride injection, USP
`mm
`immediately prior to
`
`intravenous administration.
`
`C. Basis for Approvability or Not—Approval Recommendation
`
`The application is approvable from a CMC perspective pending a) satisfactory responses
`to the deficiencies identified in this review, and b) an adequate response to the Master
`File Deficiency detailed in S. Khushboo’s letter (10/12/2010) to the drug substance
`manufacturer,
`M4). Acceptable cGMP recommendations
`have been received from the Office of Compliance for three of the four manufacturing
`and testing facilities. An inspection has been scheduled for the drug substance
`manufacturer.
`
`The applicant filed the NDA as a 505(b)(2) application for a new dosage form of
`levothyroxine sodium. The applicant’s product has been marketed in the US. as an
`unapproved drug. The FDA recently categorized Levothyroxine Sodium for Injection a
`“Marketed Unapproved Drug,” thus requiring submission of an NDA and FDA approval
`
`Reference ID: 2895223
`
`Page 9 0f 63
`
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`

`
`
`Executive Summary Section
`
`in order to keep the product on the market. This was communicated to the applicant in a
`Warning Letter issued by the FDA Chicago District on December 18, 2006. A pre-IND
`meeting was held with the Agency on March 18, 2008.
`
`The drug substance (levothyroxine sodium) will be manufactured for commercial use by
`we with most of the CMC parameters provided in
`
`the
`DMF No- A copy of the letter of authorization to reference
`
`DMF
`has been provided. No response has yet been received to the MF deficiency
`letter sent to the DMF holder on 10/12/2010. T