CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202231Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`
`From
`
`Dra - os Roman MD
`
`Recommended:
`
`Cross-Discipline Team Leader Review for an intravenous
`Subject
`
`levothyroxine product
`202-231
`
`NDA/BLA #
`
`0
`Sn n ilement#
`
`Applicant
`APP Pharmaceuticals, LLC
`Date of Submission
`Au st 30, 2010
`
`PDUFA Goal Date
`
`June 30, 2010
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Levothyroxine Sodium for Injection] Levothyroxme
`Sodium for In'ection
`
`Dosage forms / Strength
`
`Pro n osed Indication 5
`
`Three presentations containing the following strengths of
`levothyroxine sodium: 100 mcg/6.5 mL vial, 200 meg/10
`mL vial, 500 me
`Treatment of m edema coma
`
`1. Introduction
`
`Levothyroxine Sodium for Injection is a marketed unapproved drug used for the treatment of
`myxedema coma and other forms of hypothyroidism in which oral levothyroxine
`administration is not feasible. On December 18, 2006, APP Pharmaceuticals, the
`
`manufacturer of Levothyroxine Sodium for Injection (and sole manufacturer of an intravenous
`levothyroxine product at this time), was notified via a Warning Letter issued by the FDA
`Chicago District that, in order to lawfully market this product, it will need to submit a New
`Drug Application. A pre-lND meeting was held with the Agency on March 18, 2008, at which
`time APP Pharmaceuticals received advice from multiple review disciplines. Specifically,
`FDA requested that, given the diversity of information available in the medical literature, the
`company provide a clear justification for the proposed dosing regimen to be labeled for the
`treatment of myxedema; in addition, the Agency requested relative bioavailability data
`between oral and intravenous (IV) levothyroxine to guide dose conversion between these two
`regimens.
`
`APP Pharmaceuticals submitted the current NDA (202-231) on August 30, 2010 under Section
`505(b)(2) of the Food, Drug, and Cosmetics Act. The preclinical, clinical pharmacology, and
`clinical sections of the NDA contain exclusively data derived from published literature. From
`an approvability standpoint two issues are central to this submission: 1) the demonstration that
`the drug substance specifications (including identity, purity, excipient characterization) meet
`Agency standards, and 2) whether the literature published with intravenous levothyroxine in
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`Page 1 of 10
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`Cross Discipline Team Leader Review
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`myxedema coma is sufl'rcient to identify a safe and effective treatment regimen, and if such
`information can be organized in a cohesive and informative label.
`
`2. Background
`
`Levothyroxine has a very long history of use in humans. Following the discovery of thyroxine
`in 1914, the elucidation of its chemical structure in 1926 and its subsequent synthesis, it has
`been used as replacement therapy for more than half a century. Intravenous formulations of
`levothyroxine have been introduced in the treatment of myxedema coma in the early 1960’s.
`
`The basic physiology of levothyroxine has been largely elucidated and is relatively well
`understood. This knowledge has its origins in an extensive body of medical literature
`spanning multiple decades of investigations and its therapeutic use is summarized in standard
`textbooks and professional society guidelines (e.g. Endocrine Society, American Thyroid
`Association). Although there are obvious differences between oral and IV levothyroxine
`products, mostly related to the route of administration, rate of absorption, and specific dosing,
`the clinical effect can be largely extrapolated from oral to intravenous products. No less
`importantly, the toxicity profile of levothyroxine in humans is well characterized on the basis
`of medical conditions of thyroid hormone excess or inappropriate use.
`
`Myxedema coma is the most severe form of hypothyroidism. It is an exceedingly rare medical
`condition - an incidence rate of 0.22 per 1,000,000 per year has been reported - with an
`associated mortality as high as 80% if left untreated. There are only approximately 300 cases
`of myxedema coma reported to date in the medical literature.
`
`At the time of NDA submission the applicant proposed the following indication:
`
`L-Thyroxine for Injection is indicated for treatment of myxedema coma,
`
`(b)(4)
`
`The Division took the position tha
`
`(m4)
`
`The applicant
`agreed and, in an amendment dated May 13, 2001, stated that “that the only indication to be
`listed on the drug product labeling is myxedema coma”.
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`Cross Discipline Team Leader Review
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`3. CMC/Device
`
`The drug substance for Levothyroxine Sodium for Injection is levothyroxine, identical in
`structure with the eponymous hormone. The drug product is a lyophilized powder containing
`levothyroxine sodium along with the following excipients: dibasic sodium phosphate
`heptahydrate, mannitol, and sodium hydroxide. It is packaged in amber glass vials (the drug
`product is photolabile) at three dosage strengths: 100 mcg/vial, 200 meg/vial and 500
`mcg/vial, and is stored at room temperature. These three dosage forms were selected with the
`goal of supporting a range of loading doses of 300—500 mcg and maintenance doses of 50 mcg
`and 100 mcg. Once reconstituted in 0.9% sodium chloride for injection, the product is to be
`used immediately (it is, in fact, stable for up to 4 hours at room temperature).
`
`The drug substance specifications were found to be acceptable by the CMC reviewer and they
`met all the requirements of the current USP monograph, as did all the excipients. In addition,
`all impurities met compendial requirements as well. A shelf-life 01
`mm was granted for
`storage at room temperature
`"m" because of
`insufficient real-time stability data.
`
`There are no CMC issues to prevent approvability. Both the primary CMC review ODI.
`Leginus; DARRTS 4/29/2011) and secondary review (Dr. Al Hakim; DARRTS 4/29/2011)
`recommend approval of the application, and there are no requests or recommendations for
`postmarketing studies. The microbiology review also recommends approval, indicating that
`no deficiencies were identified regarding the sterility of the drug product. Finally, the CMC
`review also indicates that “acceptable cGMP recommendations have been received from the
`Office of Compliance for all manufacturing and testing facilities.”
`
`4. Nonclinical Pharmacology/1'oxicology
`
`The applicant did not conduct any pharmacology, pharmacokinetics, or toxicology animal
`studies with Levothyroxine Sodium for Injection. Instead, the nonclinical data presented in
`this application summarizes information from published literature, most of which was obtained
`with levothyroxine administered via routes other than IV. The reviewer comments that in the
`absence of toxicokinetic information it is difficult to predict human exposure and toxicity. On
`the other hand, the absence of a clear relationship between toxic animal doses and proposed
`human doses is counterbalanced by information provided by clinical experience in humans
`(which is quite extensive), by the fact that IV levothyroxine is administered to patients in a
`controlled hospital setting for a condition characterized by low or absent endogenous
`levothyroxine and, very importantly, by the mode of administration which involves titration to
`a desired pharmacodynamic and clinical response.
`
`It is anticipated that the toxicity profile of intravenous levothyroxine in humans will be
`dictated by the exaggerated pharmacological effect of levothyroxine (i.e. symptoms of
`hyperthyroidism) and/or the impurity profile. While with respect to the former, appropriate
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`Cross Discipline Team Leader Review
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`human dose selection and careful clinical monitoring should prevent such toxicity. Regarding
`the latter, the impurities identified in the drug product were all found to be within acceptable
`limits, and no animal studies were felt to be needed in order to further characterize them. In
`final analysis, the pharmacology/toxicology reviewer recommends approval of Levothyroxine
`Sodium for Injection for the treatment of myxedema coma.
`
`In addition, one needs to acknowledge that the role of a preclinical toxicology program for a
`product whose active moiety is a small molecule identical structurally to an endogenous
`hormone, as is the case with levothyroxine (or other hormones for that matter), is different
`when compared to a chemical compound for which there is no human counterpart. Such
`difference exists not only because we understand better the physiological and pharmacological
`effects of a native product but, even more so, because of the availability of human
`“toxicology” data provided by pathological conditions of hormone excess, such as
`hyperthyroidism. In such cases the CMC confirmation of identity and purity is a considerable
`step in providing reassurance on the safety of the product.
`
`
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`
`The clinical pharmacology review recommends approval of the application. As was the case
`with the preclinical pharmacology/toxicology section of the submission, the applicant did not
`conduct any clinical pharmacology studies, relying instead exclusively on published literature.
`
`Analysis of the published information indicates that, once injected, levothyroxine distributes
`rapidly to target tissues and is indistinguishable from endogenous levothyroxine. It has a
`relatively long half-life (6 – 8 days for euthyroid patients and 9 – 10 days for myxedema
`patients) primarily due to the fact that > 99% of plasma levothyroxine is protein bound, which
`protects it from rapid degradation and excretion. Only unbound hormone is metabolically
`active. The major metabolic pathway of degradation is sequential deiodination that occurs in
`the thyroid, liver, kidneys, placenta and fibroblasts. Another route of degradation is hepatic
`glucuronidation and sulfation, followed by excretion into the bile and intestine from which it
`can be recirculated enterohepatically. The major route of excretion is renal, and only 20% is
`eliminated in the stool.
`
`The pharmacodynamic response in myxedema coma is illustrated in Figure 4 of the clinical
`pharmacology review1, which depicts the time course of TSH reduction following the
`administration of a levothyroxine dose (428 mcg) at the upper end of the proposed
`levothyroxine starting dose (300-500 mcg). A 32% reduction in TSH of is observed within 24
`hours of IV levothyroxine administration; the TSH reduction continued during maintenance
`
`
`1 Reproduced from Ridgeway EC, McCammon JA, Benotti J, et al. Acute metabolic responses in myxedema to
`large doses of intravenous L-thyroxine. Ann Intern Med 1972;77:549-555.
`
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`Cross Discipline Team Leader Review
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`treatment with subsequent daily intravenous doses of 100 mcg of levothyroxine (the proposed
`regimen is 50-100 mcg).
`
`
`
`
`
`The clinical pharmacology review addresses at length the issue of relative bioavailability (BA)
`of oral levothyroxine and IV levothyroxine and whether a BA study with an approved oral
`levothyroxine product is necessary for approval. The review points out that under CFR 320.21
`there is a regulatory requirement for providing bioavailability information. The review also
`emphasizes the importance of having accurate information for converting the intravenous
`levothyroxine dose to an oral levothyroxine dose.
`
`In the end, the clinical pharmacology reviewer recommends waiving the requirement for a BA
`study “for good cause” (CFR 320.22(e)). I agree with this recommendation which is made
`with the explicit goal of ensuring an uninterrupted supply of IV levothyroxine to physicians
`who treat patients with myxedema coma, a true endocrine emergency with mortality as high as
`80% if left untreated. On the other hand, my stricto sensu reading of the regulations is that
`under 320.21 in vivo bioavailability can be waived for products for which bioavailability is
`self-evident, as is the case of “a parenteral solution intended solely for administration by
`injection” (which appears to be the specific case for Levothyroxine Sodium for Injection).
`
`With respect to the issue of conversion of the intravenous dose to an oral dose, I agree with the
`point made that a bioavailability study with a currently marketed oral formulation is desirable,
`but it needs to be acknowledged that in the clinical setting conversion of IV levothyroxine to
`oral levothyroxine is not an issue since the clinical norm is to use a conversion ratio of 1:2.
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`Cross Discipline Team Leader Review
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`This 50% conversion rule is a rather conservative approach, some references2 indicating a 66%
`to 72% relative bioavailability with older oral levothyroxine products. Equally important, this
`dose conversion is not expected to provide an “ultimate” oral dose but rather a transition
`regimen that is further adjusted, optimized and individualized by titration to biochemical and
`clinical response, depending on the underlying etiology of hypothyroidism.
`
`
`
`6. Clinical Microbiology
`
`
`Not applicable.
`
`
`7. Clinical/Statistical- Efficacy
`
`
`
`The evidence of efficacy is provided exclusively from published literature and consists mostly
`in case reports, case series, meta-analyses, and reviews, and only occasionally prospective
`data; as such, there is no statistical review for this application. Dr. Lowys’s clinical review
`refers to 45 literature articles that the applicant submitted to support a determination of
`efficacy for Levothyroxine Sodium for Injection in myxedema coma (12 of them refer
`primarily to either oral levothyroxine or to triiodotyronine). Given that in myxedema coma
`levothyroxine is used to replace a missing or insufficient endogenous hormone, the central
`issue from a clinical standpoint is that of identifying a dose regimen that reverses the state of
`deficiency, while delivering a dose free of the known toxicities associated with levothyroxine
`excess. Therefore, this section of the memorandum will touch on both efficacy and safety
`issues. This memorandum will not reiterate the arguments that support the superiority of
`intravenous levothyroxine regimens over intravenous triiodothyronine regimens; this issue is
`not directly related to the proposed labeling claims of this particular application; it is, however,
`of general interest and is discussed by Dr. Lowy in the clinical review.
`
`The published literature provides ample and convincing evidence that intravenous
`levothyroxine is an effective treatment for myxedema coma. Intravenous levothyroxine has
`changed the outcome for myxedema coma from a mortality rate up to 80% to approximately
`80% survival (data vary between different reports depending of the severity of myxedema at
`the time of intervention, the presence and the severity of comorbidities, and the specific dosing
`regimen selected). Several dosing regimens have been investigated since the early 1960s when
`the efficacy of intravenously administered levothyroxine was demonstrated in a study in which
`all seven patients with myxedema coma survived after receiving 120-500 mcg (average dose
`411 mcg) of levothyroxine3. Historically, the initial dose regimens have been selected on the
`basis of information accumulated from basic physiology studies which allowed an estimation
`of a total body pool of levothyroxine of 360 mcg and a daily turnover of 50-80 mcg in
`
`2 Maxon et al. (Int J Clin Pharmacol Ther Toxicol 1983;21:379-82)
`3 Holvey DN, Goodner CJ, Nicoloff JT, et al. Treatment of myxedema coma with intravenous thyroxine.
`Arch Intern Med 1964;113:89-96.
`
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`euthyroid patients. Based on such information, patients received levothyroxine doses that
`attempted to meet physiological needs or replace deficits. For instance, a 500 mcg loading
`dose was estimated to restore levothyroxine levels to about half of the euthyroid value and
`such a dose and higher doses (e.g. 750 - 1000 mcg) were investigated4. Following
`administration of an intravenous loading dose of levothyroxine, clinical changes in vital signs
`are noticed after 6-12 hours; due to the long half-life of the hormone, peak metabolic effect
`occurs after 10-12 days.
`
`Once clinical experience has accumulated, it became evident that loading doses > 500 mcg
`were in fact excessive, did not provide additional efficacy benefits, and were associated with
`undesired adverse events, particularly coronary ischemia, myocardial infarction, and
`arrhythmias. Additional data indicated that some subgroups of patients, such as the elderly
`and patients with underlying cardiac disease, while not having different efficacy requirements,
`were at higher risk for severe outcomes, and conventional wisdom dictated that in such
`patients treatment should be initiated at the lower end of the effective doses. The consensus
`that is emerging among authors is that doses > 500 mcg daily are unsafe and that lower dose
`regimens (300-500 mcg or even lower) are desirable. It is in fact a loading dose of 300-500
`mcg that the applicant proposes for the Levothyroxine Sodium for Injection label, and in her
`review Dr. Lowy concurs.
`
`Following the selection and administration of a loading dose, levothyroxine treatment
`continues with a daily “maintenance” intravenous dose for a variable period of time until
`patients recover enough to be considered for oral levothyroxine replacement; at that time the
`IV dose is converted to an equivalent oral dose. Although the issue of selecting maintenance
`doses is discussed less frequently in the published literature (conceivably because a narrower
`range of doses and less controversial dosage regimens have been explored), there appears to be
`general agreement that daily maintenance doses of 50-100 mcg are effective and reasonably
`safe. The conversion of the IV levothyroxine dose to an oral dose has been already discussed
`in Section 5 of this memorandum.
`
`It should be also recognized that transition from IV levothyroxine to oral administration during
`the treatment of myxedema coma is different from converting an oral levothyroxine product to
`IV levothyroxine in a patient who is currently euthyroid but cannot receive oral thyroxine
`because of an intervening condition that precludes oral drug administration (e.g. severe or
`persistent gastrointestinal illness, surgery, critical illnesses, etc). In such situations a more
`precise knowledge of levothyroxine’s bioavailability will be necessary to prevent under- or
`over-estimating the IV dose, which in either scenario may have serious clinical consequences
`to the patient. This is a situation that may be encountered in clinical practice and, until the
`applicant conducts a bioavailability study to address this issue, a limitation of use should be
`included in the drug label to make prescribers aware of this existing dosing limitation. Should
`the sponsor conduct a relative bioavailability study in euthyroid patients, and should such a
`study be approved, the limitation of use will no longer be necessary and should be removed
`from the label.
`
`
`
`4 Ridgeway EC, McCammon JA, Benotti J, et al. Acute metabolic responses in myxedema to large doses of
`intravenous L-thyroxine. Ann Intern Med 1972;77:549-555.
`
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`(b) (4)
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`Cross Discipline Team Leader Review
`
`8. Safety
`
`Generally speaking, the human toxicity profile of Levothyroxine Sodium for Injection is
`expected to be that of hyperthyroidism5 if the product is administered at excessive doses. In
`this context, the known effect of levothyroxine on cardiovascular function, which may result in
`tachycardia, arrhythmias, myocardial ischemia and infarction, or worsening of congestive
`heart failure, is of particular importance. These complications are expected to be an issue
`particularly in patients with underlying cardiac disease and in the elderly, who have a limited
`cardiac reserve.
`
`The safety information submitted in this NDA confirms the above expectations. The NDA
`summarizes safety data from 40 clinical studies, although not all of them were specific to the
`IV delivery route. It is noteworthy that loading doses as high as 1000 mcg had been used
`before the safety profile of IV levothyroxine was established. An increased risk of
`cardiovascular adverse events with doses greater than 500 mcg is amply documented and
`therefore such excessive doses should not be approved (see also Dr. Lowy’s analysis of the
`published safety information in Table 3 titled “Clinical Safety Studies Reported in the
`Literature” and Table 4, “Listing of Deaths in Reports Using IV Levothyroxine”). The dosing
`regimen already discussed in Section 7 of this memorandum already reflects these safety
`concerns, including those specific to the elderly and to patients with coexisting cardiac disease.
`
`In recognition of the fact that the dose regimen needs to be individualized, the “Dosage and
`Administration” Section of the label has language indicating that age, general physical
`condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema
`symptoms need to be considered when determining the starting and maintenance dosages of
`Levothyroxine Sodium for Injection. In addition, reflecting the safety observations made in
`different patient populations, the Warning and Precautions Section of the label indicate that in
`patients at risk (elderly and those with existing cardiac disease) dosing has to be started
`cautiously. I do not believe that these warnings should be carried fmther into a Boxed
`Warning because patients with myxedema coma are cared in specialized settings with good
`monitoring (ICUs) by highly qualified and knowledgeable practitioners.
`
`Finally, I am in agreement with Dr. Lowy that the dose regimen proposed reaches a reasonable
`balance between safety and efficacy.
`
`Palpitations, tachycardia, nervousness. tremors. msomma, heat intolerance. sweating. abdominal cramps.
`diarrhea, increased appetite. elevated blood pressure, angina pectoris. fever, menstrual irregularities, weight loss.
`etc.
`
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`Cross Discipline Team Leader Review
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`9. Advisory Committee Meeting
`
`
`There were no Advisory Committee meetings
`
`
`10.
`
`Pediatrics
`
`
`The application received a waiver for pediatric studies under PREA because myxedema is
`exclusively an adult disease without a pediatric counterpart.
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`
`None.
`
`
`12.
`
`Labeling
`
` A
`
` final labeling has been negotiated with the applicant and will not be reproduced in this
`memorandum. The relevant efficacy, safety and dose-selection comments made in this
`memorandum have been addressed in the label.
`
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`
`Levothyroxine Sodium for Injection should be approved for the indication of treatment of
`myxedema.
`
`
`• Risk Benefit Assessment
`
`
`The risk benefit ratio is favorable for the proposed dosing regimen (300-500 mcg initial
`loading dose followed by 50-100 daily mcg administrations until patients have recovered and
`are expected to tolerate oral levothyroxine). As indicated in the body of this memorandum
`(and reflected in the finalized drug label) it is recommended that this dosing regimen be
`individualized, particularly in patients with risk factors such as advanced age and existing
`cardiovascular disease.
`
`
`
`
`None.
`
`• Recommendation for Postmarketing Risk Evaluation and Management Strategies
`
`• Recommendation for other Postmarketing Requirements and Commitments
`
`
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`Cross Discipline Team Leader Review
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`
`None.
`
`
`• Recommended Comments to Applicant
`
`Because your application did not provide enough information to guide conversion from an oral
`to an intravenous (IV) levothyroxine regimen for hypothyroid patients who are controlled on
`oral levothyroxine products but require temporarily IV replacement, as discussed in the May
`11, 2011 teleconference, we encourage you to conduct a bioavailability study addressing the
`issue of oral to IV dose conversion. The results of such a study may be submitted as an
`efficacy supplemen
`
`
`
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`(b) (4)
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DRAGOS G ROMAN
`06/02/2011
`
`MARY H PARKS
`06/02/2011
`Concur with Dr. Roman's recommendations
`
`Reference ID: 2954983
`
`