CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`202231Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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`NDA
`Submission Dates
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`OCP Division
`OND Division
`Sponsor
`Formulation; Strengths
`Relevant IND
`Indications
`
`
`
`CLINICAL PHARMACOLOGY REVIEW
`202-231
`August 30, 2010 and December 20, 2010
`To be determined
`Levothyroxine sodium
`S.W. Johnny Lau, R.Ph., Ph.D.
`Sally Y. Choe, Ph.D.
`Clinical Pharmacology 2 (HFD 870)
`Metabolism and Endocrinology Products (HFD 510)
`APP Pharmaceuticals
`Intravenous injection; 100, 200, and 500 μg/vial
`101,385
`Treat myxedema coma
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`Table of Contents
` Executive Summary
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`1.1 Recommendations
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`1.2 Post Marketing Requirement or Post Marketing Commitment
`1.3 Summary of Important Clinical Pharmacology Findings
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` Question Based Review
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`2.1 Bioavailability Requirement
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`2.2 General Attributes
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`2.3 General Clinical Pharmacology
`2.4 Intrinsic Factors
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`2.5 Extrinsic Factors
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`2.6 Biopharmaceutics
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`2.7 Bioanalytical
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`3 Labeling Comments
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`1 Executive Summary
`The sponsor is currently the sole supplier of levothyroxine sodium injection (200 and 500 μg/vial) to treat
`hypothyroid patients.
`
`The Food and Drug Administration (FDA) categorized levothyroxine sodium injection a “Marketed
`Unapproved Drug,” thus requiring a New Drug Application (NDA) submission and an approval in order
`to continue marketing the product. The sponsor received such an FDA Warning Letter on December 18,
`2006. In compliance with the requirement, the sponsor submitted a 505(b)(2) NDA for their
`levothyroxine sodium injection without conducting any clinical studies to seek an approval for the
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`indications of the treatment of myxedema coma,
` The sponsor relies only on published literature to support this NDA.
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`Reference ID: 2946952
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`1
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`(b) (4)
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`(b) (4)
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`

`

`•
`
`1.1 Recommendations
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP2) has reviewed
`NDA 202-231’s Clinical Pharmacology data and finds it acceptable.
`
`1.2 Post Marketing Requirement or Post Marketing Commitment
`None.
`
`1.3 Summary of Important Clinical Pharmacology Findings
`Although the sponsor did not conduct any study to demonstrate the in vivo bioavailability of their
`levothyroxine sodium injection and there is no FDA-approved levothyroxine sodium injection for the
`sponsor to refer, the requirement of in vivo bioavailability data for the sponsor’s levothyroxine sodium
`injection may be waived for good cause so as to protect the public health per the CFR Section 320.22(e),
`since levothyroxine sodium injection is a medically necessary drug and is intravenously administered.
`
`The review team mulled over the need of relative bioavailability information between intravenous
`levothyroxine sodium injection and oral levothyroxine sodium product so as to help clinicians transition
`patients from intravenous to oral dosing. For myxedema coma patients, the need for this relative
`bioavailability information is not as critical since:
`•
`In clinical practice, it is generally understood that the intravenous dose is typically 50% of the oral
`dose. Therefore, clinicians can follow this practice when initiating oral levothyroxine.
`In general, when initiating oral levothyroxine, it is standard of care to reassess a patient clinically
`and with laboratory data at a minimum of 6 weeks after the drug is started. Therefore, unless a
`patient did not follow-up with their clinician, it would be unlikely that a patient would remain at a
`suboptimal oral dose for an extended period of time.
`
`
`Thus, the relative bioavailability information between intravenous levothyroxine sodium injection and
`oral levothyroxine sodium product is “nice to have” and not “need to have” for myxedema coma patients.
`However, this relative levothyroxine bioavailability information may be critical for other indications such
`as hypothyroid patients who temporarily cannot take oral levothyroxine sodium products and have to be
`transitioned to intravenous administration.
`
`Upon intravenous administration, levothyroxine rapidly distributes to tissues. Levothyroxine is more than
`99% plasma protein bound, which protects the hormone from metabolism and excretion as well as
`resulting in a long half-life in the systemic circulation (about 6 – 8 days for euthyroid patients and 9 – 10
`days for myxedema patients). The major pathway of thyroid hormone metabolism is via sequential
`deiodination. Thyroid hormones are primarily eliminated by the kidneys.
`
`Both published mechanistic and clinical studies support the proposed intravenous levothyroxine sodium
`initial loading dose of 300 – 500 μg and maintenance dose of 50 – 100 μg once daily for myxedema
`coma.
`
`
`
`________________________
`S.W. Johnny Lau, R.Ph., Ph.D.
`OCP/DCP2
`
`
`
`
`Reference ID: 2946952
`
`2
`
`

`

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`
`
`FT signed by Sally Y. Choe, Ph.D., Team Leader, 5/ /11
`
`An Office Level Clinical Pharmacology Briefing for NDA 202-231 was conducted on April 29, 2011; participants included N.
`Lowy, D. Roman, A. Rahman, G. Burckart, L. Lesko, H. Ahn, D. Abernethy, L. Galgay, C. Sahajwalla, L. Jain, C. Shukla, J.
`Leginus, A. Agrawal, Z. Li, L. Zhao, K. Reynolds, R. Jain, I. Zadezensky, S. Naraharisetti, A. Khandelwal, Y. Mulugeta, J-E
`Lee, J. Bishai, S. Choe, and J. Lau.
`
`
`
`Reference ID: 2946952
`
`3
`
`

`

`2 Question-Based Review
`The sponsor did not conduct any clinical pharmacology study and they relied only on published literature
`to support NDA 202-231.
`
`2.1 Bioavailability Requirement
`What is the requirement for the bioavailability of levothyroxine sodium injection?
`
`Regulatory Requirement
`Per the Code of Federal Regulation (CFR) 320.21 “Requirements for submission of bioavailability and
`bioequivalence data.”
`(a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall
`include in the application either:
`(1) Evidence measuring the in vivo bioavailability of the drug product that is the subject of the application;
`or
`(2) Information to permit FDA to waive the submission of evidence measuring in vivo bioavailability.
`
`The sponsor does not have any in vivo bioavailability data for their levothyroxine sodium injection and by
`submitting the literature data, (2)’s waiver option can be applicable. Since this product is a parenteral
`solution intended solely for administration by injection, the following CFR can be applicable to the
`waiver:
`CFR 320.22 “Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.”
`(b) For certain drug products, the in vivo bioavailability or bioequivalence of the drug product may be self-
`evident. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the
`bioavailability or demonstrating the bioequivalence of these drug products. A drug product's in vivo
`bioavailability or bioequivalence may be considered self-evident based on other data in the application if
`the product meets one of the following criteria:
`(1) The drug product:
`(i) Is a parenteral solution intended solely for administration by injection, or an ophthalmic or otic solution;
`and
`(ii) Contains the same active and inactive ingredients in the same concentration as a drug product that
`is the subject of an approved full new drug application or abbreviated new drug application.
`The missing critical information for this NDA is the underlined portion of the last 2 lines above. Because
`there is no approved levothyroxine sodium injection product as reference, this waiver is not applicable.
`Thus, the sponsor needs to conduct a study to characterize the bioavailability of their levothyroxine
`sodium injection to satisfy the CFR 320.21.
`
`The Sponsor’s Submission
`The sponsor cited the Maxon et al. article (see Question 2.6.1 below) to provide the relative
`bioavailability data between SYNTHROID intravenous injection and SYNTHROID oral tablet as well as
`LEVOTHROID oral tablet (Int J Clin Pharmacol Ther Toxicol 1983;21:379-82). The Maxon et al. article could have
`provided the sponsor’s to-be-marketed levothyroxine sodium injection bioavailability data via linking it to
`the oral levothyroxine bioavailability data. However, the NDA approval dates for SYNTHROID and
`LEVOTHROID oral tablets are July 24, 2002 and October 24, 2002, respectively (Drugs@FDA). Thus,
`Maxon et al. studied unapproved SYNTHROID and LEVOTHROID oral tablets before August 21, 1983
`(publication date). Had the sponsor studied any approved oral levothyroxine products, they may satisfy
`the waiver requirement via linking the bioavailability of levothyroxine sodium injection to the
`bioavailability of an approved oral levothyroxine product(s).
`
`
`
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`Reference ID: 2946952
`
`4
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`

`

`The Sponsor, APP Pharmaceuticals, is currently the sole source of levothyroxine injection and therefore is
`supplying all intravenous levothyroxine demand of this medically necessary drug (Clinical Filing Checklist,
`October 19, 2010).
`
`Balancing the need of the above issues, the Review Team recommended filing this NDA and Clinical
`Pharmacology requested the sponsor to respond to the following:
`“We have noted that there is no drug exposure information of an approved levothyroxine injection product in your submission.
`If you have any information or data addressing this or any relative exposure information of your product comparing to that of
`an approved levothyroxine product (i.e., either injection product or oral tablet product), submit those information by December
`20, 2010.”
`
`The sponsor confirmed on December 20, 2010 that the NDA does not contain “clinical drug exposure data
`for an approved levothyroxine injection product” because no such FDA approved product currently exists.
`
`The Office of Clinical Pharmacology’s Recommendations
`CFR 320.22 “Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.”
`(e) FDA, for good cause, may waive a requirement for the submission of evidence of in vivo
`bioavailability or bioequivalence if waiver is compatible with the protection of the public health. For full
`new drug applications, FDA may defer a requirement for the submission of evidence of in vivo
`bioavailability if deferral is compatible with the protection of the public health.
`
`The Office of Clinical Pharmacology recommends a waiver for the sponsor to submit the in vivo
`bioavailability data of their levothyroxine sodium injection for good cause so as to protect the public
`health per the CFR Section 320.22(e), since levothyroxine sodium injection is a medically necessary drug
`and is intravenously administered.
`
`The review team mulled over the need of relative bioavailability information between intravenous
`levothyroxine sodium injection and oral levothyroxine sodium product so as to help clinicians transition
`patients from intravenous to oral dosing. For myxedema coma patients, the need for this relative
`bioavailability information is not as critical since:
`•
`In clinical practice, it is generally understood that the intravenous dose is typically 50% of the oral
`dose. Therefore, clinicians can follow this practice when initiating oral levothyroxine.
`In general, when initiating oral levothyroxine, it is standard of care to reassess a patient clinically
`and with laboratory data at a minimum of 6 weeks after the drug is started. Therefore, unless a
`patient did not follow-up with their clinician, it would be unlikely that a patient would remain at a
`suboptimal oral dose for an extended period of time.
`
`
`Thus, the relative bioavailability information between intravenous levothyroxine sodium injection and
`oral levothyroxine sodium product is “nice to have” and not “need to have” for myxedema coma patients.
`However, this relative levothyroxine bioavailability information may be critical for other indications such
`as hypothyroid patients who temporarily cannot take oral levothyroxine sodium products and have to be
`transitioned to intravenous administration.
`
`•
`
`
`
`Reference ID: 2946952
`
`5
`
`

`

`2.2 General Attributes
`2.2.1 What are levothyroxine sodium’s key physicochemical properties?
`Figure 1. Levothyroxine sodium’s molecular structure.
`
`
`Levothyroxine sodium has a molecular weight of 798.85, empirical formula of C15H10I4NNaO4, and
`solubility of 15 mg/100 mL in water. Levothyroxine sodium has pKa values of 2.2, 6.7, and 10.1 and has
`1 chiral center. The L-form of thyroxine is the active pharmaceutical ingredient.
`
`2.2.2 What is the formulation for the to-be-marketed levothyroxine sodium injection?
`Table 1. The to-be-marketed levothyroxine sodium injection formulation for the 100 μg strength.
`Levothyroxine Sodium for
`Unit Dose
`Exhibit Batches
`Injection
`
`Proposed
`Commercial Batch
`
`Strength
`Packaging Configuration
`Product Code
`Batch Size (L)
`Batch Size (vials)
`Ingredient
`
`Levothyroxine Sodium, USP
`Dibasic Sodium Phosphate,
`Heptahydrate, USP
`Mannitol, USP
`Sodium Hydroxide, NF
`
`
`
`
`Sodium Hydroxide, NF
`
`
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`
`
`Reference ID: 2946952
`
`100 mcg/vial
`100 mcg in a 6.5–mL vial
`506107
`
`Ingredient
`Amount/Batch
`
`Ingredient
`Amount/Batch
`
`N/A
`N/A
`Ingredient
`Amount/mL
`100 mcg
`
`6
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Proposed
`Commercial Batch
`
`200 mcg/vial
`200 mcg in a 10–mL vial
`24710
`
`N/A
`N/A
`Ingredient
`Amount/mL
`200 mcg
`
`Ingredient
`Amount/Batch
`
`Ingredient
`Amount/Batch
`
`Table 2. The to-be-marketed levothyroxine sodium injection formulation for the 200 μg strength.
`Levothyroxine Sodium for
`Unit Dose
`Exhibit Batches
`Injection
`Strength
`Packaging Configuration
`Product Code
`Batch Size (L)
`Batch Size (vials)
`Ingredient
`
`Levothyroxine Sodium, USP
`Dibasic Sodium Phosphate,
`Heptahydrate, USP
`Mannitol, USP
`Sodium Hydroxide, NF
`
`
`
`
`Sodium Hydroxide, NF
`
`
`
`Table 3. The to-be-marketed levothyroxine sodium injection formulation for the 500 μg strength.
`Levothyroxine Sodium for
`Unit Dose
`Exhibit Batches
`Injection
`
`Proposed
`Commercial Batch
`
`Strength
`Packaging Configuration
`Product Code
`Batch Size (L)
`Batch Size (vials)
`Ingredient
`
`Levothyroxine Sodium, USP
`Dibasic Sodium Phosphate,
`Heptahydrate, USP
`Mannitol, USP
`Sodium Hydroxide, NF
`
`
`
`
`Sodium Hydroxide, NF
`
`
`
`
`
`
`Reference ID: 2946952
`
`500 mcg/vial
`500 mcg in a 10–mL vial
`24810
`
`Ingredient
`Amount/Batch
`
`Ingredient
`Amount/Batch
`
`N/A
`N/A
`Ingredient
`Amount/mL
`500 mcg
`
`7
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

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`Tables 4. Explanation of the to-be-marketed levothyroxine sodium injection formulation.
`Sponsor’s Error! Reference source not found.
`Inactive Ingredients
`Dibasic Sodium Phosphate Heptahydrate, USP
`Mannitol, USP
`Sodium Hydroxide, NF
`
`Function of Inactive Ingredients
`
`
`
`
`Theoretical amount of Levothyroxine Sodium, USP required for the batch.
`
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`1
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`2
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`2.2.3 How does levothyroxine sodium injection work for the proposed indications?
`Levothyroxine sodium injection works as a thyroid hormone replacement therapy for hypothyroidism.
`
`2.2.4 What are the sponsor’s proposed indication and dosing regimen for levothyroxine injection?
`The proposed indications for levothyroxine sodium injection are the treatments of the following:
`• myxedema coma
`
`The proposed dosing regimen for the intravenous levothyroxine sodium injection is the following:
`• 300 – 500 μg as the initial loading dose
`• 50 – 100 μg once daily as the maintenance doses until the patient can tolerate oral therapy
`
`
`2.3 General Clinical Pharmacology
`2.3.1 What are levothyroxine’s clinical pharmacokinetic (PK) characteristics?
`Absorption
`The route of administration for levothyroxine sodium injection is intravenous. Upon administration, the
`administered synthetic levothyroxine is not distinguishable from the endogenous levothyroxine.
`
`Distribution — Plasma proteins bound more than 99% of circulating thyroid hormones. These proteins
`include thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA),
`whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for
`levothyroxine partially explains the higher serum concentrations, slower metabolic clearance, and longer
`half-life of levothyroxine compared to liothyronine. Protein-bound thyroid hormones exist in reverse
`equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many
`drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins. Thyroid
`hormones do not readily cross the placental barrier.
`
`Metabolism — Elimination of levothyroxine is slow (see Table 6). The major metabolic pathway of
`thyroid hormone is via sequential deiodination. About 80% of circulating T3 comes from peripheral
`levothyroxine monodeiodination. The liver is the major site of degradation for both levothyroxine and
`liothyronine, with levothyroxine deiodination also occurring at a number of additional sites, including the
`kidney and other tissues. About 80% of the daily levothyroxine dose is deiodinated to yield equal
`
`8
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`Reference ID: 2946952
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`t½ (days)
`
`Protein Binding (%)¶
`
`amounts of liothyronine and reverse liothyronine. Liothyronine and reverse liothyronine are further
`deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with
`glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic
`recirculation.
`
`Table 6. Pharmacokinetic parameters of thyroid hormones in euthyroid patients
`Hormone
`Ratio in
`Biologic
`Thyroglobulin
`Potency
`6 – 8‡
`10—20
`1
`Levothyroxine
`≤ 2
`1
`Liothyronine
`4
` ‡ 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism;; ¶Includes TBG, TBPA, and TBA
`These t½ values are from the Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th ed, Chapter 39,
`Thyroid and Anti-thyroid Drugs. This textbook’s earlier editions (before the 10th ed) stated that euthyroid
`patients’ t½ is 6 – 7 days. Also, this textbook does not state the route of administration for these t½ values.
`However, these t½ values are consistent with the mean levothyroxine t½ reported by Sterling and Chodos
`(J Clin Invest 1956;35:806-13), 6.7, 4.4, and 9.7 days, respectively, for normal, thyrotoxicosis, and myxedema
`patients upon intravenous administration of I131 levothyroxine.
`
`
`Excretion — Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated
`hormone reaches the colon unchanged and appears in the feces. About 20% of levothyroxine is
`eliminated in the stool. Urinary excretion of levothyroxine decreases with age.
`
`The above information is modified from the recently approved label of a levothyroxine sodium tablet
`(http://www.accessdata fda.gov/drugsatfda docs/label/2011/021301s027lbl.pdf).
`
`2.3.2 Is levothyroxine PK dose-proportional upon intravenous administration?
`The sponsor claimed that intravenous levothyroxine shows dose proportional PK per Table 7’s data on
`their December 20, 2010 submission.
`
`Table 7. Levothyroxine dose and exposure summary.
`Average Free‡ T4 Cmax
`Number of Patients
`
`Dose (μg)
`Reference¶
`Exposed
`(μg/dL)
`?
`5.0
`100
`17
`5*
`Maxon et al.
`5.0
`182
`
`?
`5.5
`200
`8
`Ridgway et al.
`10.0
`428
`6
`?
`11.9
`750
`7
`Arlot et al.
`19.0
`1000
`2
`
`
`Mean Dose = 433
`Total Exposures = 46
`*Healthy subjects; ‡Reviewer noticed that this should be total rather than free T4 Cmax as stated in Summary of Clinical Pharmacology
`Studies’ Table 2.7.2-3; ¶Reviewer added this column to track the references; ?Reviewer could not confirm the data with reference.
`
`99.96
`99.5
`
`
`
`Reference ID: 2946952
`
`9
`
`

`

`Figure 2. Linear relationship between dose and Can: of levothyroxine.
`
`Dose Proportionality Assessment of T4 Cmax
`
`thanT4emu,
`
`ugML
`
`NDose.uu(oneeachfromdifferentstufies)
`
`The sponsor provided inadequate data to assess intravenous levothyroxine PK dose proportionality
`because:
`
`— Each dose is from a different study, which has different input rate and thus affect Cm.
`— AUC data are also necessary to determine PK dose proportionality besides Cmax data.
`— Each Cm is a mean value and does not reflect its variability.
`— The dose and Cmax values may be from a mix of single-dose and multiple-dose studies.
`
`2.3.3 Do multiple intravenous administrations alter levothyroxine PK?
`The exposure of levothyroxine shows gradual accumulation upon multiple-dose intravenous
`levothyroxine daily administration, which is consistent with levothyroxine’s tie of 9 — 10 days (Ladenson et
`al. Am JMed 1982;73:467—74 and Ridgway et al. Ann Intem Med 1972;77:549-55).
`
`2.3.4 How are the proposed daily intravenous levothyroxine sodium injection dosing regimen
`determined for myxedema coma patients?
`Hovey et al. (Arch Intem Med 1964: 113:89-96) assumed the extrathyroid organic iodide pool is grossly
`depleted in myxedema patients and averages 245 pg/1.73 m2, whereas that for euthyroid individuals
`averages 490 pg/1.73 m2. Iodine comprises of 65.4% of levothyroxine by weight. Thus, a myxedema
`patient would have an average deficit of about 360 pg levothyroxine, which is consistent with the
`proposed intravenous loading dose of 300 — 500 pg levothyroxine sodium.
`
`The fractional hormonal turnover rate is about 11% or 50 — 60 pg of hormonal iodine daily in euthyroid
`
`individuals. The fractional levothyroxine turnover rate is about 7% or 15 — 20 pg of hormonal iodine
`daily in myxedema patients. Repletion of the hormonal pool with large doses of levothyroxine does not
`
`restore the turnover rate to normal immediately. Intravenous administration of 500 pg levothyroxine to a
`myxedema coma patient would result in the initial utilization of an added 25 pg hormonal iodine daily.
`
`To restore the minimal euthyroid state, the average myxedema patient would need 40 — 50 pg hormonal
`iodine daily. This corresponds to 61 — 76 pg levothyroxine daily, which is consistent with the proposed
`intravenous maintenance dose of 50 — 100 pg levothyroxine sodium daily.
`
`10
`
`Reference ID: 2946952
`
`

`

`
`Table 8. Literature recommendations on the levothyroxine dosing regimen for myxedema coma.
`Intravenous Loading Dose
`Intravenous Daily Maintenance Dose
`300 – 500 μg
`50 – 100 μg
`300 – 500 μg
`50 – 100 μg
`100 – 500 μg
`75 – 100 μg
`300 μg
`50 – 200 μg
`300 – 500 μg
`75 – 125 μg
`
`Reference
`Mitchell et al. Emerg Med Clin North Am
`1989;7:885-902
`Fliers et al. Rev Endocr Metab Disord
`2003;4:137-41
`C.R. Wall (Am Fam Physician
`2000;62:2485-90
`J.D. Bagdale (Med Clin North Am
`1986;70:1111-28
`D.S. Cooper’s chapter “Thyroid hormone
`replacement therapy for primary and
`secondary hypothyroidism” in Wayne
`Meike’s “Endocrine replacement therapy
`in clinical practice” book, 2003 ed; this
`reviewer’s citation
`
`
`Both published mechanistic and clinical studies support the proposed intravenous levothyroxine sodium
`initial loading dose of 300 – 500 μg and maintenance dose of 50 – 100 μg once daily.
`
`2.3.5 Exposure-Response
`What is the evidence of exposure-response relationship for intravenous levothyroxine?
`With the gradual increase in serum levothyroxine concentrations upon intravenous 100 μg levothyroxine
`daily dosing, there is the consistent decrease in serum thyrotrophin (TSH) concentrations as evidenced in
`10 hypothyroid patients, Figure 3 (Ladenson et al. Am J Med 1982;73:467-74) and Figure 4 (Ridgway et al. Ann
`Intern Med 1972;77:549-55):
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`Reference ID: 2946952
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`11
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`COPYRIGHT MATERIAL
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`These observations are consistent with the pharmacological action that TSH secretion will decrease upon
`the rise in serum levothyroxine concentrations.
`
`2.3.6 Does levothyroxine sodium injection prolong the QT or QTc interval?
`This submission does not contain any QTc data for the assessment of QT prolongation.
`
`2.4 Intrinsic Factors
`
`2.4.1 What intrinsic factors may affect the use of levothyroxine sodium injection?
`Pediatric
`
`Levothyroxine sodium injection has very limited applicability to treat myxedema coma in all pediatIic
`aged patients since the pathophysiology of the disease occurs primaril
`in the elderl
`ulation.
`However the 'ustification of atho h siolo
`
`
`
`PeRC (Pediatric Review Committee) recommended the following for levothyroxine sodium injection per
`the meeting on April 13, 2011:
`0
`a full waiver for the sponsor to conduct pediatric study on the myxedema coma indication because
`the pathophysiology primarily occurs in the elderly population
`
`
`
` no Proposed Pediatric Study Request for pediatric PK study is necessary since the patient
`population will likely to be too small and levothyroxine dosing is titrated for safety
`
`Reference ID: 2946952
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`12
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`

`Geriatric
`Myxedema coma occurs almost exclusively during or after the 6th decade with 80% of the cases occurring
`in women (C.G. Olsen’s J Am Board Fam Pract 1995;8:376-83). Olsen recommended a loading dose of 250 –
`500 μg (sic; mg in original text) levothyroxine for a 30 – 60 second intravenous administration and then
`follow with oral 100 – 170 μg (sic) daily maintenance dose. Elderly patients require a lower dose of
`levothyroxine since its degradation rate declines with aging.
`
`Yamamoto et al. (Thyroid 1999;9:1167-75) also recommended elderly myxedema coma patients to be treated
`with low-dose levothyroxine.
`
`2.4.2 What pharmacogenomic information is in the application?
`This submission does not contain any pharmacogenomic data.
`
`2.5 Extrinsic Factors
`What are the potential drug-drug interactions for levothyroxine injection?
`See the Labeling Comments section below for Section 12.3’s drug interactions. Also, Surks and Sievert’s
`review (New Eng J Med 1995;333:1688-94) contains the discussion on drug interactions with thyroid drugs.
`
`2.6 Biopharmaceutics
`What is the relative levothyroxine bioavailability upon intravenous and oral administration?
`The sponsor cited the Maxon et al. article (Int J Clin Pharmacol Ther Toxicol 1983;21:379-82) to show the
`relative levothyroxine bioavailability between intravenous and oral administration in 21 healthy
`volunteers. Briefly, this was a parallel single-dose study with the following 4 treatments:
`•
`IV SYNTHROID injection
`• Oral solution (IV SYNTHROID injection)
`• Oral SYNTHROID tablet
`• Oral LEVOTHROID tablet
`Maxon et al. used radioimmunoassay to quantitate serum levothyroxine concentrations. The relative oral
`bioavailability results follow (Table 9):
`
`Intravenous Injection as Reference
`Oral Solution
`88%
`LEVOTHROID Oral Tablet
`72%
`SYNTHROID Oral Tablet
`66%
`
`2.7 Bioanalytical
`Are the bioanalytical methods properly validated for this NDA?
`Not applicable since the sponsor did not conduct any clinical pharmacology study.
`
`3. Labeling Comments
`The yellow highlighted parts are Clinical Pharmacology’s labeling recommendations.
`
`Oral Solution as Reference
`-
`81.5%
`74.5%
`
`
`
`Reference ID: 2946952
`
`13
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`18 Page(s) of Draft Labeling has been Withheld in Full
`as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`S. W. JOHNNY W LAU
`05/13/2011
`
`SALLY Y CHOE
`05/14/2011
`
`Reference ID: 2946952
`
`

`

`CLINICAL PHARMACOLOGY
` FILING CHECKLIST FOR NDA 20-2231
`
`Applicant: APP Pharmaceuticals Stamp Date: August 30, 2010
`
`
`NDA Number: 20-2231
`Drug Name: Levothyroxine
`Sodium
`
`On initial overview of the NDA application for RTF:
`
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`NDA Type: Standard
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`Yes No
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`Comment
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`X
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`NA
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`NA
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`NA
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`NA
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`NA
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`NA
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`NA
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`Content Parameter
`Criteria for Refusal to File (RTF)
`1
`Has the applicant submitted bioequivalence data
`comparing to-be-marketed product(s) and those used in
`the pivotal clinical trials?
`Has the applicant provided metabolism and drug-drug
`interaction information?
`Criteria for Assessing Quality of an NDA
` Data
`3
`Are the data sets, as requested during pre-submission
`discussions, submitted in the appropriate format (e.g.
`CDISC)?
`If applicable, are the pharmacogenomic data sets
`submitted in the appropriate format?
` Studies and Analyses
`5
`Has the applicant made an appropriate attempt to
`determine the reasonable dose individualization strategy
`for this product (i.e., appropriately designed and
`analyzed dose-ranging or pivotal studies)?
`Did the applicant follow the scientific advice provided
`regarding matters related to dose selection?
`Are the appropriate exposure-response (for desired and
`undesired effects) analyses conducted and submitted in a
`format as described in the Exposure-Response
`guidance?
`Is there an adequate attempt by the applicant to use
`exposure-response relationships in order to assess the
`need for dose adjustments for intrinsic/extrinsic factors
`that might affect the pharmacokinetic or
`pharmacodynamics?
`Are the pediatric exclusivity studies adequately
`designed to demonstrate effectiveness, if the drug is
`indeed effective?
`10 Did the applicant submit all the pediatric exclusivity
`data, as described in the WR?
`Is the appropriate pharmacokinetic information
`submitted?
`Is there adequate information on the pharmacokinetics
`and exposure-response in the clinical pharmacology
`section of the label?
` General
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`2
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`4
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`11
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`12
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`Reference ID: 2862016
`
`

`

`14
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`CLINICAL PHARMACOLOGY
` FILING CHECKLIST FOR NDA 20-2231
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`Yes
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`Yes
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`Yes
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`Yes
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`NA
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`13 On its face, is the clinical pharmacology and
`biopharmaceutical section of the NDA organized in a
`manner to allow substantive review to begin?
`Is the clinical pharmacology and biopharmaceutical
`section of the NDA indexed and paginated in a manner
`to allow substantive review to begin?
`15 On its face, is the clinical pharmacology and
`biopharmaceutical section of the NDA legible so that a
`substantive review can begin?
`16 Are the clinical pharmacology and biopharmaceutical
`studies of appropriate design and breadth of
`investigation to meet basic requirements for
`approvability of this product?
`17 Was the translation from another language important or
`needed for publication?
`
`
`IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION
`FILEABLE? ___Yes_____
`
`If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and
`provide comments to be sent to the Applicant.
`
`
`S. W. Johnny Lau, R.Ph., Ph.D.
`
`Reviewing Pharmacologist
`
`Sally Y. Choe, Ph.D.
`Team Leader/Supervisor
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`Date
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`Date
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`Reference ID: 2862016
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`

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`CLINICAL PHARMACOLOGY
` FILING CHECKLIST FOR NDA 20-2231
`
`
`
`
`
`
`NDA
`OCP Division
`Medical Division
`OCP Reviewer
`OCP Team Leader
`Date of Submission
`
`Office of Clinical Pharmacology
`New Drug Application Filing and Review Form
`General Information About the Submission
`Information
`
`20-2231
`Brand Name
`2
`Generic Name
`DMEP, HFD-510
`Drug Class
`S.W. Johnny Lau
`Indication(s)
`Sally Y. Choe
`Dosage Form
`30-AUG-2010
`Dosing Regimen
`
`Information
`
`
`
`To-be-determined
`Levothyroxine sodium
`Thyroid hormone
`Treat myxedema
`Sterile lyophilized drug product for injection
`300 – 500 µg loading dose then 50 – 100 µg once
`daily maintenance dose
`Intravenous
`
`Estimated Due Date of OCP
`Review
`PDUFA Due Date
`Division Due Date
`
`
`
`
`
`
`
`
`STUDY TYPE
`Table of Contents present and
`sufficient to locate reports, tables, data,
`etc.
`Tabular Listing of All Human Studies
`HPK Summary
`Labeling
`Reference Bioanalytical and Analytical
`Methods
`I. Clinical Pharmacology
` In vivo mass balance:
` In vitro isozyme characterization:
`