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

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 202,231
`Priority or Standard Standard
`
`Submit Date(s) August 30, 2010
`Received Date(s) August 31, 2010
`PDUFA Goal Date June 30, 2011
`Division / Office DMEP/OND II
`
`Reviewer Name(s) Naomi Lowy, MD
`Review Completion Date May 11, 2011
`
`Established Name Levothyroxine sodium for
`injection
`(Proposed) Trade Name Levothyroxine sodium for
`injection
`Therapeutic Class Thyroid hormone
`Applicant APP Pharmaceuticals, LLC
`
`Formulation(s)
`Injection
`Dosing Regimen Initial loading dose of 300-500
`µg IV followed by daily
`maintenance doses of 50-100
`mcg until oral therapy is
`tolerated
`Indication(s) Treatment of myxedema coma
`Intended Population(s) Adults
`
`Reference ID: 2945760
`
`

`

`Template Version: March 6, 2009
`
`
`
`
`Reference ID: 2945760
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 7
`1.1 Recommendation on Regulatory Action ............................................................. 7
`1.2 Risk Benefit Assessment.................................................................................... 8
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 9
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 9
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9
`2.1 Product Information ............................................................................................ 9
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 9
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 9
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 10
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 10
`2.6 Other Relevant Background Information .......................................................... 10
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 10
`3.1 Submission Quality and Integrity ...................................................................... 11
`3.2 Compliance with Good Clinical Practices ......................................................... 11
`3.3 Financial Disclosures........................................................................................ 11
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 11
`4.1 Chemistry Manufacturing and Controls ............................................................ 11
`4.2 Clinical Microbiology......................................................................................... 11
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 11
`4.4 Clinical Pharmacology...................................................................................... 12
`4.4.1 Mechanism of Action.................................................................................. 12
`4.4.2 Pharmacodynamics.................................................................................... 12
`4.4.3 Pharmacokinetics....................................................................................... 12
`5 SOURCES OF CLINICAL DATA............................................................................ 12
`5.1 Tables of Studies/Clinical Trials ....................................................................... 12
`5.2 Review Strategy ............................................................................................... 12
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 13
`6 REVIEW OF EFFICACY......................................................................................... 13
`Efficacy Summary...................................................................................................... 13
`6.1
`Indication .......................................................................................................... 14
`6.1.1 Methods ..................................................................................................... 15
`6.1.2 Demographics............................................................................................ 15
`7 REVIEW OF SAFETY............................................................................................. 24
`Safety Summary ........................................................................................................ 24
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`Reference ID: 2945760
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`3
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`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`
`7.1 Methods............................................................................................................ 24
`7.2 Adequacy of Safety Assessments .................................................................... 26
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 26
`7.3 Major Safety Results ........................................................................................ 26
`7.3.1 Deaths........................................................................................................ 31
`7.3.4 Significant Adverse Events ........................................................................ 32
`7.4 Supportive Safety Results ................................................................................ 32
`7.5.1 Dose Dependency for Adverse Events ...................................................... 32
`7.5.2 Time Dependency for Adverse Events....................................................... 33
`7.5.4 Drug-Disease Interactions.......................................................................... 33
`7.5.5 Drug-Drug Interactions............................................................................... 33
`7.6 Additional Safety Evaluations ........................................................................... 33
`7.6.1 Human Carcinogenicity.............................................................................. 33
`7.6.2 Human Reproduction and Pregnancy Data................................................ 33
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 33
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 34
`8 POSTMARKET EXPERIENCE............................................................................... 34
`9 APPENDICES ........................................................................................................ 35
`9.1 Literature Review/References .......................................................................... 35
`9.2 Labeling Recommendations ............................................................................. 35
`9.3 Advisory Committee Meeting............................................................................ 54
`
`
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`Reference ID: 2945760
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`4
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`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`
`Table of Tables
`
`Table 1 Clinical Efficacy Studies Reported in the Literature.......................................... 16
`Table 2 Doses of Thyroid Hormone Administered in the First Week............................. 23
`Table 3 Clinical Safety Studies Reported in the Literature ............................................ 27
`Table 4 Listing of Deaths in Reports Using IV Levothyroxine........................................ 31
`
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`Reference ID: 2945760
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`5
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`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`
`Table of Figures
`Error! No table of figures entries found.
`
`Reference ID: 2945760
`
`6
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`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`1 Recommendations/Risk Benefit Assessment
`
`Levothyroxine Sodium for Injection (IV levothyroxine) is a marketed, unapproved drug
`now proposed for the treatment of “myxedema coma,
`“m
`In order to comply with
`the Agency requirement of submitting a New Drug Application (NDA) in order to obtain
`FDA approvalz, the Sponsor now submits a 505(b)(2) application relying solely on
`medical literature. The proposed dosage is an initial loading dose between 300 to 500
`pg followed by daily maintenance doses between 50 and 100 pg until the patient can
`tolerate oral therapy.
`
`Levothyroxine is approved as an oral formulation under many trade names and
`available as a generic drug. Oral levothyroxine products are indicated for the treatment
`of hypothyroidism and pituitary TSH suppression, but the label for these products state
`that, because of unpredictable absorption of levothyroxine from the gastrointestinal tract
`in a severely hypothyroid state, oral thyroid hormone drug products are not
`recommended to treat myxedema coma.
`In this respect, IV levothyroxine is considered
`a bridge, a temporary treatment, until oral therapy can be initiated.
`
`There are currently no intravenous levothyroxine formulations approved in the US.
`
`1.1 Recommendation on Regulatory Action
`
`| recommend approval of Levothyroxine sodium for injection for the treatment of
`myxedema coma.
`
`“m
`
`following recommendations, however, apply to this approval:
`0 At the time this Review was written, labeling negotiations have not commenced
`with the Sponsor. This Reviewer’s suggested revisions are included at the end
`of this Document.
`
`0 Because the Sponsor did not conduct a bioavailability study for this product, the
`Division recommends language in the label alerting providers to this lack of data
`when transitioning patients from IV levothyroxine to an oral product. Conversely,
`the Division recommends caution when switching patients from oral to IV
`levothyroxine.
`
`The
`
`1 From Sponsor’s proposed label, submitted with NDA August 31, 2010
`2 FDA Warning Letter issued by FDA Chicago District on December 18, 2006
`
`Reference ID: 2945760
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`1.2 Risk Benefit Assessment
`
`Although oral levothyroxine is available for the treatment of hypothyroidism, it is not
`indicated for the treatment of myxedema coma, since in this condition rapidly-acting
`treatment that avoids the need for gastrointestinal absorption is required.
`
`The Sponsor submitted literature to support the safety and efficacy of IV levothyroxine.
`This includes 45 clinical efficacy studies and 34 efficacy/safety studies. The Sponsor
`has not performed any clinical trials.
`
`Efficacy
`Because of the rarity of the condition as well as the acceptance of intravenous
`levothyroxine as the standard of care for the condition, conducting a randomized clinical
`trial for patients with myxedema coma is impractical if not impossible. However, the
`literature submitted in this application supports the efficacy of IV levothyroxine for the
`treatment of patients with myxedema coma. The first series of myxedematous patients
`treated with IV levothyroxine was reported in 1964.i The articles submitted in this
`application--which included case reports, case series, meta-analyses, and reviews—
`collectively confirm the efficacy and necessity of IV levothyroxine for the treatment of
`patients with myxedema coma.
`
`Safety
`The safety profile of oral levothyroxine products is well-characterized and generally
`applies to the intravenous formulation. The Sponsor submitted literature to characterize
`the safety profile of IV levothyroxine. Specifically, IV levothyroxine is associated with
`cardiac toxicity, including arrhythmia and myocardial infarction, for high doses and in the
`elderly and in those with underlying cardiac disease. Cautious use of IV levothyroxine,
`including not exceeding the recommended dose and careful monitoring in at-risk
`populations, can limit these adverse events.
`
`Proposed dose
`For the indication of myxedema coma, the Sponsor proposes an initial loading dose of
`300 to 500 µg followed by daily maintenance doses between 50 to 100 µg, until the
`patient can tolerate oral therapy. Based on the literature, this Reviewer agrees with the
`recommended dose ranges.
`
`The Sponsor has provided limited bioavailability data to aid in the transition from IV to
`oral levothyroxine therapy. A more detailed discussion of this is under Clinical
`Pharmacology.
`
`Limitations
`A prominent limitation in this application was the complete reliance on literature.
`However, the literature was sufficient to support the efficacy and safety of IV
`levothyroxine. The literature was not sufficient to provide important bioavailability data,
`
`Reference ID: 2945760
`
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`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`leading to cautionary language in the label, discussed under Efficacy and Labeling
`Recommendations.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`Not applicable to this Application.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`Not applicable to this Application.
`
` 2
`
` Introduction and Regulatory Background
`
`
`The Agency informed the Sponsor in 1996 that Levothyroxine Sodium for Injection is
`categorized as a “Marketed Unapproved Drug”. This followed the publication of the
`FDA Guidance entitled “Marketed Unapproved Drugs—Compliance Policy Guide”ii.
`
`The Sponsor met with the Division on March 18, 2008 to discus their intention of
`submitting a 505(b)(2) NDA for levothyroxine sodium for injection.
`
`
`2.1 Product Information
`
`Levothyroxine sodium for injection contains synthetic crystalline levothyroxine sodium.
`The drug product is a sterile, lyophilized powder to be reconstituted in saline. It is
`available in 3 different strengths (100 µg /vial, 200 µg /vial, and 500 µg /vial) in single-
`use vials.
`
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`There are currently no approved intravenous (IV) formulations of levothyroxine.
`
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`IV levothyroxine is currently marketed in the US.
`
`
`Reference ID: 2945760
`
`9
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`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`Not applicable to this application.
`
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
` A
`
` Pre-IND/NDA meeting between the Division and the Sponsor was held on March 18,
`2008. Key discussion and points of agreement included:
`• Given the wide variety of dosing recommendations in the literature, the Sponsor
`would need to propose and justify an appropriate dosing regimen for the
`treatment of myxedema coma.
`• Because the proposed IV formulation serves as a bridge during acute illness,
`knowledge of relative bioavailability is important. Therefore a single-dose
`crossover pharmacokinetic study, comparing the proposed to-be-marketed IV
`levothyroxine to a marketed oral levothyroxine tablet, was recommended by the
`Division.
`
`
`In a post-meeting decision conveyed to the Sponsor, the Division recommended that
`regarding bioavailability data, the Sponsor should consider conducting a single IV
`pharmacokinetic (PK) study with their product or providing the data based on literature.
`The literature data the Sponsor submitted with the meeting background package was
`not sufficient to characterize the PK of IV levothyroxine.
`
`
`2.6 Other Relevant Background Information
`
`In the clinical spectrum of hypothyroidism, myxedema coma is the most extreme form.
`Because of the difficulty in promptly recognizing and treating affected patients, the
`diagnosis carries a high mortality. Thought to be rare today, there are approximately
`300 cases reported in the literature.iii Since hypothyroidism in general is more common
`in women and in the elderly, it is believed that most patients who present with
`myxedema coma are elderly women. In a patient who presents with signs and
`symptoms of hypothyroidism with mental status changes, the diagnosis depends on a
`determination of thyroid-stimulating hormone (TSH). Once the diagnosis is made,
`therapy should be instituted immediately. Even so, the mortality rate approaches 50%
`to 60%.
`
`
` Ethics and Good Clinical Practices
`
` 3
`
`
`
`Reference ID: 2945760
`
`10
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`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`3.1 Submission Quality and Integrity
`
`Overall, the submission quality is adequate. Because of the nature of this application,
`the Sponsor, in prior agreement with the Division, did not submit Integrated Summaries
`for either safety or efficacy. Rather, the literature upon which was the Application is
`based is presented in a Summary of Clinical Efficacy and a Summary of Clinical Safety.
`
`
`3.2 Compliance with Good Clinical Practices
`
`
`Not applicable to this application.
`
`
`3.3 Financial Disclosures
`
`Not applicable to this application.
`
` 4
`
` Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`
`
`4.1 Chemistry Manufacturing and Controls
`
`Refer to Dr. Leginus’ Review for full details. There are no major approvability issues.
`
`
`4.2 Clinical Microbiology
`
`
`Refer to Dr. Mello’s Review for details. There are no approvability issues.
`
`
`4.3 Preclinical Pharmacology/Toxicology
`
`
`Refer to Dr. Tsai-Turton’s Review for full details. There are no approvability issues.
`
`
`Reference ID: 2945760
`
`11
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`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`4.4 Clinical Pharmacology
`
`Refer to Dr. Johnny Lau’s Review for full details. Information in this Section is extracted
`from his Review.
`
`
`4.4.1 Mechanism of Action
`
`Levothyroxine sodium for injection is identical to endogenous levothyroxine. Both
`thyroid hormone, thyroxine (T3) and triiodothyronine (T4) have important effects on
`development, growth, and metabolism.iv
`
`
`4.4.2 Pharmacodynamics
`
`There is a consistent exposure-response relationship, with a decrease in TSH upon
`repeated dosing of levothyroxine.
`
`4.4.3 Pharmacokinetics
`
`Once administered, the synthetic levothyroxine is indistinguishable from endogenous
`levothyroxine. More than 99% of thyroid hormone is bound by plasma proteins, but only
`the unbound hormone is metabolically active. The binding of thyroid hormone to serum
`proteins is affected by many drugs and physiologic conditions.
`
`Elimination of levothyroxine is slow with a half-life of 6 to 8 days. The major site of
`levothyroxine degradation is the liver, where it is deiodinated to liothyronine. Thyroid
`hormone primarily undergoes renal excretion with some fecal elimination.
`
` Sources of Clinical Data
`
` 5
`
`
`
`5.1 Tables of Studies/Clinical Trials
`
`
`The literature submitted by the Sponsor is summarized in Tables under Efficacy and
`Safety, below.
`
`5.2 Review Strategy
`
`The articles submitted in support of both safety and efficacy of IV levothyroxine were
`individually reviewed. Articles discussing oral levothyroxine alone or the use of
`
`Reference ID: 2945760
`
`12
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`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`triiodothyronine (T3) alone were not reviewed in detail, as they were not directly
`pertinent to this application. The vast majority of submitted literature pertained to the
`treatment of myxedema coma, and therefore the emphasis of the literature review was
`placed on this indication. The Sponsor submitted few articles relevant to the use of IV
`levothyroxine in non-myxedema coma patients.
`
`In addition, findings from this Reviewer’s own literature search are referenced
`periodically in this document and overall were consistent with data derived from the
`Sponsor’s submitted literature.
`
`
`5.3 Discussion of Individual Studies/Clinical Trials
`
`There were no Sponsor-conducted studies or trials performed to support this
`application. All data submitted is derived from literature, discussed under Efficacy and
`Safety below.
`
` 6
`
` Review of Efficacy
`Efficacy Summary
`The Sponsor’s support for efficacy of IV levothyroxine is based on 45 articles from the
`literature. These include case series, reviews, and trials primarily discussing the
`treatment of myxedema coma. Twelve of the 45 discuss the use of either oral
`levothyroxine or T3 (oral or IV) and therefore are not subject to a detailed discussion in
`this Review. For each paper submitted, the table below details the type of literature, the
`number of subjects studies (for case series and trials), and pertinent efficacy results.
`Papers considered pivotal for this discussion are discussed in greater detail following
`the table.
`
`The data, including collective observations, recommendations, and anecdotal
`experience, support the efficacy of IV levothyroxine for the treatment of myxedema
`coma. The observations and recommendations derived from the literature yield a range
`of recommended doses pertaining to the treatment of myxedema coma.
`
`With the exception of the administration of excessive doses of IV T4 (defined by this
`Reviewer as exceeding 500 µg IV), most studies show that IV T4 therapy is effective in
`doses up to 500 µg daily. A number of Authors discussed below, including Jordan,
`Bagdade, Mazzaferri, Smallridge, Olsen, Wall, and Fliers, all agree that treatment of
`myxedema coma should be initiated with an IV bolus of between 300 and 500 µg.
`Although there are some who recommend an initial IV bolus of less than 300 µg, no
`Author recommends a dose exceeding above 500 µg. Given the fairly narrow spectrum
`of opinions and conclusions, a range of 300-500 µg as an initial IV dose appears
`
`Reference ID: 2945760
`
`13
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`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`effective and allows for the practice of the art of medicine. With this recommendation,
`the clinician can then decide if a patient requires and can tolerate a dose on the lower or
`higher end of the proposed recommended range.
`
`Maintenance dosing, daily doses that follow the initial IV bolus, is discussed less
`frequently in the published literature. Among the Authors who did discuss it, there
`appears to be agreement that daily maintenance doses of 50-100 pg are effective, until
`oral doses can be tolerated.
`
`Since IV levothyroxine is intended as a temporary treatment, it would be important for a
`clinician to know how to transition a patient to oral therapy. However, because a
`bioavailability study was not performed, this information can only be construed from the
`literature, which also offers limited data using unapproved levothyroxine formulations.
`Two older studies demonstrate that absorption of the oral dose varies from 48-74% of
`the intravenous dose.Wi Differences in absorption primarily account for the wide range
`of values, and a clinician would need to cautiously use this data on a case-by-case
`basis, combined with repeated measurements of thyroid function and clinical
`assessments.
`
`Therefore, although such bioavailability data would be useful, it is not critical for the
`following reasons:
`0
`In clinical practice, a general idea of the conversion from IV to oral, based on
`limited literature,
`is understood.
`
`0
`
`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 dose for an
`extended period of time.
`
`6.1 Indication
`
`The Sponsor proposes levothyroxine for injection “for treatment of myxedema game,
`
`The use of levothyroxine for injection for the treatment of myxedema coma is the
`primary subject of discussion in this Review.
`
`The medical literature does not recognize
`and therefore this Review does not discuss it further.
`
`“M
`
`(It) (4)
`
`Myxedema coma is the end stage of untreated
`or inadequately treated hypothyroidism and the physical findings are not specific.“ “m
`
`Reference ID: 2945760
`
`14
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`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`(I!) (4)
`
`lmportantly, the Sponsor is not seeking an indication for treating patients on chronic oral
`levothyroxine therapy who require temporary lV levothyroxine, a use that is likely more
`common than myxedema coma. The Sponsor did not conduct a bioavailability study to
`yield data that is important when converting a patient from oral to IV levothyroxine.
`
`6-1.1 Methods
`
`All literature in support of efficacy is included in Table 1. Literature included in the table
`encompasses observational studies, case studies, and reviews. Because of the
`limitations associated with studying a rare disease such as myxedema coma, this body
`of summarized literature serves to collectively support the efficacy of levothyroxine for
`injection.
`
`Following Table 1 is a more in-depth discussion of articles which this Reviewer
`considers particularly vital in this application that is wholly reliant in literature. Because
`of the unusual nature of this application, including a lack of results from a dedicated
`clinical trial, template sections are omitted when non-applicable.
`
`In general, the case series and meta-analyses submitted utilized similar tools in
`assessing efficacy. These included measurements of thyroid function tests and clinical
`assessments, such as vital signs, level of consciousness, and ultimately survival, to
`assess efficacy of the designated treatment.
`
`6-1.2 Demographics
`
`The Sponsor summarized demographic data for the published articles that contained
`original clinical data related to the use of IV levothyroxine. Not all articles reported
`patient age and/or sex. For patients with myxedema coma, the age range of treated
`subjects was 20—90 years. However, the subjects were predominantly elderly women.
`In the Sponsor’s database, there was only one treated patient under the age of 30
`years, a 20 year old man with typhoid fever (Rodriguez, 2004).
`
`Reference ID: 2945760
`
`1 5
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`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`Table 1 Clinical Efficacy Studies Reported in the Literature
`Author
`Indication
`Literature
`studied
`category
`Myxedema coma Case Series
`
`Rawson, 1953viii
`
`Products
`used/discussed
`T4 3 mg IV versus
`T3 1 mg IV
`
`No. of
`subjects
`1
`
`Holvey, 1964ix
`
`Myxedema coma Case Series
`
`T4 120-500 µg IV
`
`7
`
`Green, 1968x
`
`Myxedema coma Guidelines
`
`T3 and T4 IV
`
`Rosenberg, 1968xi Myxedema coma Review
`
`Senior, 1971xii
`
`Myxedema coma Case Series
`and Discussion
`
`T4 500 µg IV
`followed by daily
`doses of T4 50-75
`µg IV.
`T4 100 µg TID IM
`
`n/a
`
`n/a
`
`1
`
`BMR, UA, Stool
`analysis, serum
`cholesterol
`
`Improved vital
`signs, return to
`consciousness
`Clinical outcome
`
`Primary endpoints Efficacy Results/Recommendations on
`Dosing
`Both products produced similar endpoints.
`However, T3 exerted a quick, short-lived
`effect, whereas L-thyroxine had a slow,
`prolonged effect.
`All patients had improvements of VS in 6-
`12 hours. All patients returned to
`consciousness in 24-36 hours.
`Initial IV doses for full replacement should
`be either T4 500 µg OR T3 120 µg.
`Early treatment should be initiated with
`either IV T4 or enteral T3 (because of risk
`of arrhythmia associated with IV T3).
`
`Physical
`examination,
`laboratory findings,
`x-rays
`Clinical outcome
`
`Patient became alert within 3 days. MC
`should be treated with 400-500 µg T4 IV
`plus hydrocortisone. T3 is associated
`with a more variable therapeutic response
`as well as cardiac toxicity.
`Author primarily recommends 500 µg of L-
`thyroxine intravenously as initial dose.
`Another option is T3 IV, 10 to 25 µg given
`every 8-12 hours.
`TSH levels decreased in both groups
`within 24 hours, but were more rapidly
`decreased in Group #2. All subjects
`reportedly tolerated the large doses well.
`
`Blum, 1972xiii
`
`Myxedema coma Review
`
`Ridgeway, 1972xiv Primary
`hypothyroidism
`
`n/a
`
`Clinical outcome
`
`Laboratory values
`
`14 total
`(7 per
`group)
`
`Less than 500 µg
`IV T4 as initial dose
`or T3 10-25 µg IV
`given 8-12 hours.
`Open-label trial 2 groups:
`1) 428 µg T4 IV
`followed by 100
`µg daily for 9
`days
`2) 750 µg T4 IV
`followed by 200
`µg daily for 9
`days
`T4 IV, T3 IV
`
`Klein, 1973xv
`
`Reference ID: 2945760
`
`Myxedema coma Letter to the
`Editor
`(response to
`
`NA
`
`Clinical endpoints
`
`The Author questions the use of high
`doses of IV thyroid hormone as well as
`the lack of complications noted.
`
`16
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`
`Author
`
`Indication
`studied
`
`Literature
`category
`Ridgeway
`1972)
`
`Products
`used/discussed
`
`No. of
`subjects
`
`Menendez, 1973xvi Myxedema coma Review
`
`T4 IV, T3 IV
`
`NA
`
`Nicoloff, 1976xvii
`
`Myxedema coma Review
`
`T4 IV
`
`NA
`
`Jordan, 1983xviii
`
`Myxedema coma Review
`
`Initial dose:
`
`n/a
`
`Reference ID: 2945760
`
`17
`
`Clinical outcomes
`
`Clinical outcome
`
`Primary endpoints Efficacy Results/Recommendations on
`Dosing
`Ridgeway responds that in the young as
`well as healthy old, large doses are likely
`warranted.
`The Author states therapy is either T3
`given by NG tube or IV T4. In an
`emergency, large doses should be given:
`400-500 µg T4 in a single dose followed
`by 50 µg IV or 0.1 mg orally daily. Also,
`T3 has been used in doses of 12.5 µg q6h
`given via NG tube. Oral and
`intramuscular absorption is uncertain
`initially. T4 is favored because it has a
`less arrhythmic effect.
`Initially, because of sluggish circulatory
`and GI concerns, all medications in MC
`should be administered the IV route. High
`doses of thyroid hormone are
`recommended. Administration of 500 µg
`IV T4 to an average-sized adult will
`restore circulating thyroxine level to about
`half the euthyroid value.
`
`IV T4 does not require a repeat dose for
`at least one week after initial
`administration. Its therapeutic margin of
`safety is much wider than that of T3.
`There are no significant adverse
`metabolic effects if a treated patient is
`subsequently found to not have
`hypothyroidism. IV T4 produces definitive
`improvement in clinical status within 6-36
`hours. Its use has shifted clinical
`outcomes from 80% mortality before the
`1960s to approximately 80% survival.
`The Author’s recommendation, based on
`
`Clinical outcomes
`
`

`

`No. of
`subjects
`
`Primary endpoints Efficacy Results/Recommendations on
`Dosing
`Ridgeway’s recommendations, is for an
`initial IV dose of 400 µg followed by 50 µg
`daily.
`
`11
`
`Mortality, estimated
`levels of T3 and T4
`
`In this retrospective study, only 4/11
`patients survived. Excessive use of T3
`was associated with a higher mortality
`rate.
`Patients should be given an initial dose of
`T4 300 µg IV followed by maintenance
`doses of 50-200 µg IV until PO
`administration is possible.
`Risk factors for mortality in MC are
`hypotension and other serious underlying
`conditions.
`
`Clinical Review
`Naomi Lowy, M.D.
`NDA 202,231
`Levothyroxine Sodium for Injection
`
`
`Author
`
`Indication
`studied
`
`Literature
`category
`
`Hylander, 1985xix
`
`Myxedema coma Meta-analysis
`
`Products
`used/discussed
`T4 400 µg IV
`
`Maintenance dose:
`T4 50 µg
`T3 (oral and IV), T4
`(oral and IV), or a
`combination
`
`Mazzaferri, 1986xxi Myxedema coma Symposium
`
`Mitchell, 1989xxii
`
`Myxedema coma Review
`
`Arlot, 1991xxiii
`
`Myxedema coma Observational
`
`Gavin, 1991xxiv
`
`Myxedema coma Review
`
`Initial dose: T4 300
`µg IV by slow
`infusion over first
`day
`
`Subsequent doses:
`T4 50 µg IV daily
`until consciousness
`is regained
`T3
`T4
`
`2 groups :
`1) T4 IV 1000 µg
`IV, or
`2) 500 µg oral T4
`followed by 100
`µg PO daily
`Initial dose : T4 IV
`500 µg IV
`
`Maintenance dose:
`T4 IV 50-100 µg
`
`18
`
`Reference ID: 2945760
`
`Bagdade, 1986xx
`
`Myxedema coma Guidelines
`
` T4 300 µg IV
`
`n/a
`
`Clinical outcomes
`
`n/a
`
`Clinical outcomes
`
`n/a
`
`Clinical outcomes
`
`7 (2 in
`Group 1
`and 5 in
`Group 2)
`
`Laboratory values,
`clinical
`improvement
`
`n/a
`
`Laboratory values
`
`Recommendations are an initial T4 IV
`dose of 300-500 µg as a bolus or slow
`infusion followed by 50-100 µg /day.
`A clinical response is seen within 36
`hours, even