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

`

`
`
`DEPARTRIENT OF HEALTH AND HURIAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADlVflNISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUIVIBER:
`
`202231
`
`000
`
`DATE RECEIVED BY CENTER:
`
`August 30tll 2010
`
`PRODUCT:
`
`Levothyroxine Sodium for Injection
`
`INIENDED CLINICAL POPULATION: Treatment for Myxedema Coma,
`
`"’""
`
`SPONSOR:
`
`APP Pharmaceuticals, LLC
`
`DOCUIVIENTS REVIEWED:
`
`EDR
`
`REVIEW DIVISION:
`
`DMEP (RFD-510)
`
`PHARM/TOX REVIEWER:
`
`Miyun Tsai—Turton, PhD, MS
`
`PHARM/TOX SUPERVISOR:
`
`Karen Davis-Bruno, PhD
`
`DIVISION DIRECTOR:
`
`Mary Parks, MI)
`
`PROJECT MANAGER:
`
`Linda Galgay
`
`Date of review submission to DARRTS: April 8“1 2011
`
`Reference ID: 2930003
`
`

`

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`
`TABLE OF CONTENTS
`
`
`EXECUTIVE SUMMARY .............................................................................................. 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................... 5
`
`2.6.1 INTRODUCTION AND DRUG HISTORY................................................................... 5
`
`2.6.2 PHARMACOLOGY......................................................................................................... 8
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY......................................................... 9
`Overview ................................................................................................................................................... 9
`Pharmacology .......................................................................................................................................... 10
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 18
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY............................................... 18
`Overview ................................................................................................................................................. 18
`Absorption ............................................................................................................................................... 19
`Distribution.............................................................................................................................................. 21
`Metabolism .............................................................................................................................................. 22
`Excretion.................................................................................................................................................. 23
`Drug-drug interactions............................................................................................................................. 24
`
`2.6.6 TOXICOLOGY .............................................................................................................. 25
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY .............................................................. 30
`Overview ................................................................................................................................................. 30
`General toxicology................................................................................................................................... 32
`Reproductive toxicity............................................................................................................................... 37
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS............................................... 58
`
`APPENDIX/ATTACHMENTS ................................................................................................. 63
`
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`Reference ID: 2930003
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`2
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`Reviewer: Miflm Tsai-Turton
`
`NDA No. 202231
`
`EXECUTIVE SUMMARY
`
`Recommendations
`
`A. Recommendation on approvability
`
`Pharam/tox recommends approval of this application.
`
`B. Recommendation for nonclinical studies
`
`No further animal studies will be needed.
`
`C. Recommendations on labeling
`
`See pharm/tox comments on labeling on pages 61-62.
`
`Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings
`
`APP Pharmaceuticals, LLC did not conduct any animal studies with
`regards to pharmacology, pharmacokinetics, or toxicology studies in
`support of their Levothyroxine Sodium for Injection. The sponsor based
`their nonclinical data on published literature through Medline and Toxnet
`databases. Currently, there are no other injectable levothyroxine products
`currently approved by the FDA. Most studies found in literature have
`different routes of exposure rather than IV, which is the intended route of
`exposure.
`
`As similar to other oral levothyroxine products, the animal toxicity of
`levothyroxine is mostly associated with expected exaggerated
`levothyroxine pharmacology (i.e. hyperthyroidism — decreased body
`weight or increased heart rate) at high doses. Because there was no
`toxicokinetic information available in the literature, it is difficult to
`
`correlate thyroid hormone toxicity with exposure or maximal
`levothyroxine concentration or relate to human exposure. On the other
`hand, since this IV levothyroxine is intended to use in hospitals for an
`acute rescue (i.e.
`(m4) myxedema
`coma]
`om) anY
`IV levothyroxine—related adverse effects (i.e. hyperthyroidism) can be
`easily monitored or reversed. Also, due to severe hypothyroid states of
`these patients, the risk of having these hyperthyroidism-associated adverse
`effects would be small, even if it is at a much higher IV dose of
`levothyroxine when compared to oral levothyroxine which is used to
`maintain thyroid hormone homeostasis.
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`Reference ID: 2930003
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`

`

`Reviewer: Miyun Tsai-Turton
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` NDA No. 202231
`
`There were several impurities identified in the drug substance/product.
`Since they are all within acceptable limits, no animal study is needed to
`further characterize these impurities.
`
`In summary, the sponsor is relying on published literature to support this
`IV levothyroxine product. Published literature seems to reveal a similar
`profile, regarding to pharmacokinetic (no apparent difference in AUC
`between an injectable and oral product) and toxicity (hyperthyroidism-
`associated adverse effects). In addition, the sponsor is relying on
`physicochemical characterization of identity as there is an absence of
`bridging animal toxicology data. Based on CMC review, both drug
`substance (referenced to DMF
` and drug products (e.g. impurities
`levels are within ICHQ3) are consistent with the monograph. Therefore,
`there is no safety nonclinical concern at this time.
`
`B. Pharmacologic activity
`
`Levothyroxine Sodium for Injection is a synthetic T4, which is identical to
`that produced in the human thyroid gland. The function of thyroid
`hormone has been well-characterized in human.
`
`C. Nonclinical safety issues relevant to clinical use
`
`The sponsor did not have any bridging animal data with their IV
`levothyroxine product. Therefore, it is not possible to directly identify any
`potential nonclinical safety issue that is specifically related to this product.
`
`Based on animal data from literature with levothyroxine and information
`from other approved oral levothyroxine products, there would be no safety
`issue except an exaggerated pharmacological effect of levothyroxine (i.e.
`hyperthyroidism) when it is overcompensated. Since this product will be
`used as hospital rescue therapy, overcompensation should not be
`problematic. This Levothyroxine Sodium for Injection by APP
`Pharmaceuticals will be the first injectable levothyroxine on the market.
`
`It seems that both IV and oral levothyroxine have very similar profiles (i.e.
`no major differences in AUC and hyperthyroidism-related toxicity).
`However, with no bridging animal data on this IV levothyroxine product,
`similarity of products would be determined by physicochemical means by
`CMC. The CMC has communicated that the characterization of both drug
`substance and drug product are consistent with the monograph.
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`Reference ID: 2930003
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`4
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`(b) (4)
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`Reviewer: Miyun Tsai-Turton
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` NDA No. 202231
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`
`
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`
`
`2.6.1 INTRODUCTION AND DRUG HISTORY
`NDA number: 202231
`Review number: 1
`Sequence number/date/type of submission: 000/August 30th, 2010/Original 505(b)(2)
`Information to sponsor: Yes ( ) No (x)
`Sponsor and/or agent: APP Pharmaceuticals, LLC
`Manufacturer for drug substance:
`
`Reviewer name: Miyun Tsai-Turton, PhD, MS
`Division name: DMEP
`HFD #: 510
`Review completion date: 04/08/2011
`
`Drug:
`
`
`
`
`
`
`Trade name: --
`Generic name: Levothyroxine Sodium for Injection
`Code name(s): 506107 (100 mcg), 24710 (200 mcg), and 24810 (500 mcg)
`Chemical name: L-tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-,
`monosodium salt
`CAS registry number: 55-03-8
`Molecular formula/molecular weight: C15H10I4NNaO4 and 798.85
`Structure:
`
`
`
`
`Relevant INDs/NDAs/DMFs:
`(cid:131) IND
`(cid:131) NDA 21-116: Levothroid (tablet)
`(cid:131) NDA 21-210: Unithroid (tablet)
`(cid:131) NDA 21-301: Levoxyl (tablet)
`(cid:131) NDA 21-342: LEVO-T (tablet) by Alara Pharm (approved on March 02’)
`(cid:131) NDA 21-402: Synthroid (tablet)
`(cid:131) NDA21-924: Tirosint (capsule)
`(cid:131) DMF
`Levothyroxine sodium, USP
`
`
`Drug class: Levothyroxine
`
`
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`Reference ID: 2930003
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`5
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA No. 202231
`Tsai—Turton
`Reviewer: Mi
`
`
`Intended clinical population:— myxedema coma.
`
`Clinical formulation: Levothyroxine Sodium, USP (100, 200, and 500 meg/vial) with
`inactive ingredients listed below. The current dose recommendation, based on PK and
`clinical data, is an initial loading dose of levothyroxine between 300 to 500 mcg,
`followed by daily maintenance doses between 50 and 100 mcg until the atient can
`. Note: Dlll‘lll
`re-IND meetin , the concem o
`
`
`
`_
`m» «mw
`
`APP’: Levothyroxine Sodium for Injection
`W
`Dflnsic scam Phosphate Heptnhydnte, USP
`Mannitol, USP
`SodimnHydroxide,Nl-'
`
`I
`I
`
`—-
`—I—-
`
`0
`
`.
`
`1” “mm. "mmg”
`
`—-
`
`——m_
`——l
`—.
`Ingredient
`Ingredient
`
`Ingredient—-—-
`
`Ingredient
`
`—-
`—I
`—-
`
`Heptnhydmte, USP
`
`Reference ID: 2930003
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`

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`NDA No. 202231
`Tsai-Tm’ton
`Reviewer: Mi
`
`
`—-
`—_-
`Ingredient
`Ingredient
`Amount/IIIL
`
`E‘
`
`Ingredient
`AmountlBatch
`
`Ingredient
`Amount/Batch
`
`I I I I I E
`
`. I—
`
`Eag
`
`:E E
`
`I.
`
`IIIIII
`
`EEE
`
`:EEE
`
`Batch Size (L)
`
`Batch Size (vhls)
`
`E?E
`
`EE EE
`
`'EEE .E‘s.'a
`
`a a
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`Reference ID: 2930003
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`
`
` IV
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` NDA No. 202231
`
`Reviewer: Miyun Tsai-Turton
`
`
`
`Route of administration:
`
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`For (b)(2) applications:
`Data reliance : Except as specifically identified below, all data and information
`discussed below and necessary for approval of NDA 202231 are owned by APP
`Pharmaceuticals or are data for which APP Pharmaceuticals has obtained a written right
`of reference. Any information or data necessary for approval of NDA 202231 that APP
`Pharmaceuticals does not own or have a written right to reference constitutes one of the
`following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness
`for a listed drug, as described in the drug’s approved labeling. Any data or information
`described or referenced below from a previously approved application that APP
`Pharmaceuticals does not own (or from FDA reviews or summaries of a previously
`approved application) is for descriptive purposes only and is not relied upon for approval
`of NDA 202231. Note: the sponsor is relying published literature to support their drug
`product. However, two oral products (Synthroid® and Levothroid®) were mentioned in
`the labeling.
`
`Studies reviewed within this submission: N/A
`
`Studies not reviewed within this submission: N/A
`
`2.6.2 PHARMACOLOGY
`
`Levothyroxine sodium for injection acts like the endogenous T4 produced naturally in the
`human thyroid gland.
`
`MOA: T4 is converted to T3, the active metabolite in the liver and kidney. To increase
`solubility, the T3 and T4 attach to thyroid hormone binding proteins, which then transport
`and bind to thyroid hormone receptors in the cytoplasm and nucleus. Therefore, by
`acting as a replacement of natural T4, symptoms of T4 deficiency are relieved. The
`pharmacologic profile of levothyroxine (T4) sodium is well established. This drug
`product is a synthetic T4.
`
`The primary functions of thyroid hormone, both T3 and T4, are to increase metabolism
`(i.e. protein synthesis), growth and development (i.e. growth hormone, bone growth, and
`neuronal maturation), and catecholamine effect (i.e. adrenaline). The sponsor provided a
`literature review, using Medline and Toxnet as two separate databases, to support the
`pharmacological profile (PD + safety pharm) of levothyroxine sodium for injection.
`These cited studies are non-GLP.
`
`The most common finding with levothyroxine is hyperthyroidism, an exaggerated
`pharmacologic response (i.e. weight loss, increased food consumption, increased heart
`
`
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`Reference ID: 2930003
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`8
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`(b) (4)
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` NDA No. 202231
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`Reviewer: Miyun Tsai-Turton
`
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`rate, increased blood pressure), in thyroid-status compromised or uncompromised
`animals (i.e. mice, rats, guinea pigs, rabbits, or dogs) via different routes (i.e.
`intraperitoneal, subcutaneous, oral, or intravenous). Some CNS (i.e. changes in
`amygdale-related behavior in adult, spatial learning, and hippocampal morphology) and
`CV findings (i.e. cardiac hypertrophy) were linked with levothyroxine to animals. All in
`all, no new findings were identified which would impact on the safety of Levothyroxine
`Sodium for Injection.
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY
`
`Overview
`
`
`
`
`
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`9
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`Pharmacology
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`(cid:131) Note: Articles in the table below were cited as Primary Pharmacodynamic studies by
`the sponsor.
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`(cid:131) Note: Articles in the next two tables below were cited as Secondary
`Pharmacodynamic studies by the sponsor except Ruiz-Marcos, et al. (1994) which was
`cited as safety pharmacology study.
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`(cid:131) Note: Articles in the next eight tables were cited as Safety Pharmacology studies by
`the sponsor.
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`(cid:131) Note: Articles in the next four tables below were cited as Secondary
`Pharmacodynamic studies by the sponsor.
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`2.6.4 PHARMACOKINETICS/TOXICOKINETICS
`
`Publications were extracted from Medline and Toxnet as two separate databases to
`support the PK/TK profile of levothyroxine sodium for injection.
`
`Several analytical methods (i.e. radioimmunoassay or electrochemiluminescence
`immunoassays) were used to generate the ADME profile of levothyroxine.
`
`Absorption (TK oral) data showed that the tmax was 3-7 hrs for tablet and solution oral
`formulations, and t½ was approx. 8.6-14.6 hrs in dogs. Distribution (placental transfer)
`data indicated that minimal placental transfer of T4 occurred in the rat during the last days
`of gestation. The metabolism data showed sodium salicylate increased the rate of T4
`disappearance from the blood and increased the update of T4 by the isolated perfused rat
`livers, as well as increased rats of conjugation of T4 with glucuronic acid. The
`elimination data showed there was the hepatobiliary clearance of T4 by hepatic
`microsomal enzyme induction, and approx. 3% of total administration dose of T4 was
`excreted into bile in rats. As similar to animals, the metabolism of T4 occurs mostly in
`the human liver. T4 can be conjugated with glucuronic and sulfuric acids and excreted in
`the bile. All in all, no new findings were identified which would impact on the safety of
`Levothyroxine Sodium for injection.
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY
`
`Overview
`
`
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`Absorption
`Note: single and repeated doses
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`Distribution
`Note: organ distribution, plasma protein binding, and PK in pregnant/nursing animals
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`Metabolism
`Note: in vivo and in vitro
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`Excretion
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`Drug-drug interactions
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`2.6.6 TOXICOLOGY
`
`Publications were extracted from Medline and Toxnet as two separate databases to
`support the toxicological profile of levothyroxine sodium for injection. These cited
`studies included single/repeat doses of levothyroxine, and studies in pregnant animals and
`their offspring. These are non-GLP studies.
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`Reference ID: 2930003
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`Reviewer: Miyun Tsai-Turton
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`There are no animal studies provided. This is the first injectable levothyroxine product
`submitted for approval. The sponsor provided published literature (some oral animal
`studies). However, the sponsor did not make any reference to other approved oral
`products in this NDA submission.
`
`
`(cid:131) Repeat dose toxicity
`
`
`Most toxicity seen in animals with levothyroxine is exaggerated pharmacological effect
`of T4. These effects include decreased body weight, increased body temperature, cardiac
`hypertrophy (increased heart mass, heart rate, and ion channel changes), decreased bone
`mineral density, increased ALT and AST, and etc.
`
`There was no study found via IV as a route of exposure.
`
`There was one oral rodent study (Subudhi et al. 2008). The male rats were given
`0.0012% in water daily for 30 days. The study focused on the role of vitamin E and
`curcumin on hyperthyroidism-induced mitochondrial oxygen consumption and oxidative
`damage to lipids and proteins of rat liver. The study suggested that both vitamin E and
`curcumin have a protective role against levothyroxine induced hepatic dysfunction (e.g.
`serum AST and ALT increases) and oxidative stress (lipid peroxidation). There was no
`NOAEL identified in this study.
`
`There were few oral non-rodent studies. One study (Le Trano et al. 2009) focused on the
`role of levothyroxine in treating hypothyroidism. The dogs were given 12-40 μg/kg daily
`for 22 weeks. The study suggested that all hypothyroid dogs had rapid clinical and
`hormonal responses to oral T4 (liquid) supplementation. The oral dose of 40 μg/kg in
`dog correlates to 0.8 mg/m2 exposure. There was no NOAEL identified in this study.
`Another dog study (Panciera et al. 1992) studied the effect of levothyroxine on
`echocardiographic and electrocardiographic measurement in euthyroid dogs. The dogs
`were given 0.5 mg/m2 (25 μg/mg) twice daily for 8 weeks. The results showed that
`levothyroxine did not affect all parameters measured (e.g. heart rate and EKG). There
`was no NOAEL identified in this study either.
`
`In addition, no toxicokinetic data was found in the literature searches. Therefore, it is
`difficult to establish the correlation between thyroid hormone toxicity findings with
`exposure (e.g. AUC or Cmax) of levothyroxine.
`
`
`(cid:131) Reproductive and developmental toxicity
`
`
`Excess levothyroxine could affect fetal and neonatal development (i.e. changes in lung
`maturation, growth stunting, and suppression of the fetal thyroid). High doses of
`levothyroxine could lead to neo-T4 syndrome, such as decreased body weight, decreased
`growth hormone, decreased TSH, and increased mortality and derangements in
`carbohydrate metabolism.
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`Reference ID: 2930003
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`Reviewer: Mim Tsai-Turton
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`NDA No. 202231
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`There was one IV pig study (Erenberg A and Rhodes 1980). The pigs were treated 50 pg
`thyroxine by bolus injection followed by a constant IV infusion of 100 pg T4/day for 72
`hours during gestation. The results suggested that low dose of T4 to euthyroid ovine
`fetuses appeared to affect the mesenchymal portion of the lung and accelerate
`alveolarization. There was no NOAEL identified and no toxicokinetics data generated in
`this study. There was no NOAEL identified and no toxicokinetics data generated in this
`study.
`
`There was one oral rodent study (Soerjodibroto et al.). The rats were given 0.1 pg of L-
`thyroxine daily for 28 days. The study focused on the effect of L-thyroxine on
`reproduction in protein-deficient rats. The study showed that physiological doses of
`thyroxine can modify intra-uterine growth (e.g. higher mean birth weight) in animals
`sufi'ering fi'om a long-term marginal protein deficiency. There was no NOAEL identified
`and no toxicokinetics data generated in this study either.
`
`I Other toxicity (e.g. genotoxicity and carcinogenicity)
`
`No genotoxicity and carcinogenicity studies were found in the published literature.
`
`No local tolerance, antigenicity, immunotoxicity or toxicity studies on
`impurities/degradants were found in the published literature.
`
`I Impurities
`
`Drug substance: There are 9 impurities identified in the drug substance by the sponsor.
`There are apparently within acceptable limits. No animal studies were conducted to
`address any impurity and degradant issues.
`Table 5.
`Regulatory Spectflcntlon for Levothyroxlne Sodlum, USP (etfectlve August 1, 2008)
`
`Acceptance Criteria
`
`Test Methodl “Lot fl 1001059
`
`:owmpows'
`
`NMT l0'.
`XMT 0.15%
`XMT 0.15%
`'.\'MT 015%
`NMT 0.20%
`NMT 0.15%
`.\'MT 0.15%
`NMT 0,159.
`NMT 0.10%
`K XMT 1.5%
`Total Aerobic Count
`Total Yeast and Mold Count
`Total Combined Biobnrden
`mm mm:
`
`3-1
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`L'SP
`10-08-01-6485
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`NMT 100 CPU 3
`Nth 100 CPU 3
`NMT 100 CPU g
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`Test
`Related Compounds
`Lrothyronine
`BHydroxyr43
`T4-Hydtoxyaceuc and"
`.‘\"-l-'orrnjt'I-‘I‘4S and T4-Acemde°
`N—Acetyl-Tf
`T4—Acetic Acid”
`
`A B
`
`.
`C.
`D.
`E,
`F.
`G.
`
`T4~Aldehyde9
`r4Benzoic Ana”
`Indtxidual Unspecified Impnrm
`Total Impurities
`Microbial Bloburden
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`H I J I
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`B-Hydroxy-‘N
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`O-(4-hydroxy-3,5-
`diodophuyD-3,5-d.iiodo-B-
`hydroxy-L-tytosine
`
`(Model-tyrosine
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`T4-Hydmxyacetic acid
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`2-hydroxy-2-(4-(4—hydroxy-
`3,5-diiodophenoxy)-3,S-
`diodcphuxylhcedc acid
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`N-Ponnyl-T4
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`N-Pounyl—O—(‘l-hydmxy-
`3,5-diiodophenyl)—3 ,5-
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`T4-Acenmide
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`2-(4-(4-hYdIOXY-35-
`diiodophenoxy)-3,5-
`diiodophenylhcetamide
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`N-Acetyl-T4
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`N.Ac.ty1.044-hyamy-3,5-
`anodophmylynM—L-
`tyrosine
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`
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`T4-Acetic Acid
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`2-(4—(4—hydroxy—3,5-
`diiodophenoxy)-3 ,5-
`diiodophenylhcetic acid
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`T4—Aldehyde
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`4—(4-hydroxy-3,5-
`diiodophuoxy)-3,5-
`diiodobennldehyde
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`T4—Benzoic Acid
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`4—(4-hydroxy-3,S-
`diiodophenoxy)-3,5-
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`Drugproduct: There were 9 batches tested. Based on Q3B(RZ) for drug product,
`Levothyroxine Sodium for Injection, if the MDD (maximum daily dose) is 0.5 mg, the
`ICH identification and qualification thresholds are 1.0%.
`
`The sponsor proposed limit on the levothyroxine assay (by HPLC) is -which is
`a wider range than the -range for oral levothyroxine products.
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`With regards to lioth onine (a metabolite of levothyroxine), all 9 batches showed similar
`results at
`There was no obvious increase over 6 months. The limit of
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`NMT! is proposed to account for potential variability from the drug substance and
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`finishe product, and based on USP limits for the drug substance and drug product (USP
`limit for API: NMT 1.0% and USP limit for Tablets: NMT 2.0%). Since the sponsor
`indicated that liothyronine is a drug metabolite and this compound is an approved drug in
`the US, the proposed limit is not a safety issue.
`
`Withregardsto allotherindividualimpurities, all9batches showedsimilarresultsat
`
`There was no obvious increase over 6 months. The limit ofNMI‘- is
`propose , according to the ICH identification threshold of 1.0%.
`
`With regards to total impurities, all 9 batches showed similar results at
`was no obvious growth over 6 months. A limit of NMT
`is propose
`the impurity limits of liothyronine and all other individ
`nnpurities.
`
`There
`y summing
`
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`Note: The wider assay range for this inj ectable product was discussed at the filing
`meeting. The proposed assay range is acceptable since this is not an oral product and is
`intended to be used in the hospital setting, where patient seium levels will be measm'ed.
`In addition, CMC has no issue with the specifications for these impurities.
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`2.6.7 TOXICOLOGY TABULATED SUMlVIARY
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`Overview
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` Spares/Strain: SpragueDawley rats Duration ofDosing: 5 days Study No.: Maeda. et al. (1986)
`
`
`Study Title: L-thyroxine, cortisol and diet nfi‘ect the
`Day of Mating: Unspecified
`Initial Age: Unspecified
`postnatal development of the facial part of the skull
`
`in developing rats
`Date of First Dose: Day 5. Day 10 or Day 15 afler birth Method of Admimstration: s.c. injection
`Location in CTD: Module 4
`
`Vehiclefonnulation. solution
`Specs] Features. Ns‘A
`61.? Compliance. No
`
`Litters Culledr’Not Culled: Unspecified
`No Observed Adverse Effect Level: N‘A
`
`F0 Females: Unspecified
`
`Fl Males: Unspecified
`
`FlFemales: Unspecified
`
`
`
`0.2 [lg/g
`L-thyroxine
`Daily Dose (mg/kg):
`0 (Control)
`
`
`-——Marlced
`G=Gestation day. L=Lactation day. -.\'o noteworthy findings.
`-.\vlild
`+~Moderate
`‘=p=10.05. "=p=10.01,
`a At end of gestation or lactation For controls. group means are shown For treated groups percent differences from controls are shown Statistical
`Significance is based on actual data (not on the percent dfferences).
`b From birth to weaning.
`‘ From weaning to mating.
`d From birth to mating,
`' At end of postweaning period For controls. group means are shown. For treated groups. percent difl'eiences from controls are shown. Statistical
`significance is based on actual data (not on the percent differences).
`
`
`
`
`
`fAt end ofpremating or gestation period, For controls. group means are shown. For treated groups, percent differences from controls are shown
`Statistical significance is based on actual data (not on the percent differences).
`NA = Not Applicable
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS
`
`APP Pharmaceuticals, LLC submitted this NDA 202231 as 505(b)(2) application for
`Levothyroxine Sodium for Injection (100, 200, and 500 meg/vial) to treat myxedema
`coma.
`me This was previously submitted as IND
`101,385 and the pre—IND meeting was held with DMEP on March 2008. The drug
`product consists of the active ingredient, levothyroxine, and inactive ingredients such as
`dibasic sodium phosphate heptahydrate, mannitol, sodium hydroxide,
`one
`one The sponsor has based the eflicacy and safety oftheir product on published
`literature. They did not conduct any animal studies (pharmacology, pharmacokinetic, or
`toxicology) in support of this drug product. All published literature cited were non-GLP
`studies.
`
`I Pharmacology and safety pharmacology of IV levothyroxine
`
`Published nonclinical pharmacology studies for myxedema coma
`dose SC and IP
`are limited. Similar physiological responses (by repeat
`administration) were observed in animals with normal thyroid activity and in those with
`hyperthyroidism. These responses include weight loss, increased food consumption,
`increased heart rates and etc. In patients with myxedema coma, these same physiological
`responses would be attenuated due to their severely hypothyroid states.
`
`In addition, there were no standard safety pharmacology evaluations of levothyroxine in
`published literature. Nonetheless, the effects of levothyroxine on CV system (i.e. cardiac
`hypertrophy) and CNS system (i.e. changes in amygdale nuclei and its related behavior,
`spatial learning, and hippocampal morphology) have been noted. There findings are
`generally an exaggerated pharmacological activity of levothyroxine. Such adverse
`effects can be seen in clinical settin s when overco
`ensated with levoth oxine.
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`Lastly, there was also no literature available with regards to IV levothyroxine-drug
`interactions. The sponsor based