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

`

`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Lyophiliz
`ed powder for injection in single use vials: 100 mcg, 200 mcg, 500
`mcg. (3)
`
`
`----------------------CONTRAINDICATIONS-------------------------------
`
`•
`
`•
`
`tration o
`f
`
`--------
`None
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`•
`Excessive bolus doses of Levothyroxine Sodium for Injection
`(> 500 mcg) are associated with cardiac complications, particularly
`in the elderly and in patients with an underlying cardiac condition
`.
`Initiate therapy with doses at the lower end of the recommended
`range. (5.1)
`Close observation of the patient following the adminis
`Levothyroxine Sodium for Injection is advised. (5.1)
`Levothyroxine Sodium for Injection therapy for patients with
`previously undiagnosed endocrine disorders, including adrenal
`insufficiency, hypopituitarism, and diabetes
`insipidus, may worsen
`symptoms of these endocrinopathies. (5.2)
`
`--------
`
`
`------------------------------ADVERSE REACTIONS-----------------------
`Excessive doses of L-thyroxine can p
`redispose to signs and symptoms
`ompatible with hyperthyroidism.
`
`c T
`
`o report SUSPECTED ADVERSE REACTIONS, contact APP
`Pharmaceuticals, LLC, Medical Affairs Department at
` 1-800-551-7176 or
` at 1-800-FDA-1088 or www.fda
`
`medwatch. .gov/
`FDA
`
`------------------------------DRUG INTERACTIONS---------------------
`Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g.,
`absorption, synthesis, secretion, catabolism, protein binding, and target tissue
`response) and may a
`lter the therapeutic response to Levothyroxine Sodium for
`Injection. (7, 12.3)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------
`•
`Elderly and those with underlying cardiovascular disease
`receive doses at the lower end of the recommended range. (8.5)
`
`should
`
`
`
`
`
`
`
`
`
`
`
`_________________________________________
`
`Revised: [June 2011]
`
`___________________________
`
`
`8.4 Pediatric Use
`8.5 Geriatric Use and Patients with Under
`lying Cardiovascular Disease
`9 DRUG ABUSE AND DEPE
`NDENCE
`9.1 Controlled Substa
`nce
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`CLINICAL PHARMACOLO
`12
`GY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairme
`13.2 Animal Toxicology
` and Pharmacology
`14 CLINICAL STUDIES
`15 REFERENCES
`HOW SUPPLIED/STORAGE
`16
`16.1 How Supplied
`16.2 Storage and Handling
`17
` PATIENT COUNSELING INFORMATION
`
`
`
`*Sectio
`ns or subsections omitted from the full prescribing information are not
`listed.
`
`
`13
`
`nt of Fertility
`
` AND HANDLING
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Levothyroxine Sodium for Injection safely and effectively. See full
`oxine Sodium for Injection.
`prescribing information for Levothyr
`
`Levothyroxine Sodium for In
`itial U.S. Approval: 1969
`In
`
`
`WARNING: NOT FOR TREATMENT OF OBESITY OR F
` WEIGHT LOSS
`See full prescribing information for complete boxed warning.
`Thyroid hormones, including Levothyroxine Sodium for Injection, should
`not be used for the treatment of obesity or for weight loss. (5.3)
`Larger doses may produce serious or even life threatening manifestations
`of toxicity. (6)
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Levothyroxine Sodium is an L-thyroxine product. Levothyroxine (T4) Sodium
`for Injection is indicated for the treat
`ment of myxedema coma. (1)
`
`Important Limitations of Use:
`The relative bioavailability of this drug has not been established. U
`when converting patients from oral to intravenous levothyroxine.
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`•
`An initial intravenous loading dose of Levothyroxine Sodium for
`Injection between 300 to 500 mcg followed by once daily intravenous
`maintenance doses between 50 and 100 mcg should be administered,
` as
`clinically indicated, until the patient can tolerate oral therapy. (2.1)
`Reconstitute the lyophilized Levothyroxine Sodium for Injection by
`aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP. Shake
`vial to ensure complete mixing. Reconstituted drug product is
`preservative free. Use
`immediately after reconstitution. Discard any
`unused portion. (2.3)
`D
`o not add to other IV fluids. (2.3)
`
`
`•
`
`•
`
`
`
`_________________________________________________
`__________________
`
`FULL PRESCRIBING INFORMATION:
`
` CONTENTS*
`
` 1
`
`s with Cardiovascular Disease
`
`
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosage
`2.2 Dosing in the Elderly and in Patient
`2.3 Reconstitution Directions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Risk of Cardiac Complic
`ations in Elderly and in Patients with
`Cardiovascular Disease
`Need for Concomitant Glucocorticoids and Mo
`nitoring for Other
`Diseases in Patients with Endocrine Diso
`rders
`5.3 Not Indicated for Trea
`tment of Obesity
`6 ADVERSE REACTIONS
`7 DRUG INTERACTIONS
`7.1 Antidiabetic Therapy
`7.2 Oral Anticoagulants
`7.3 Digitalis Glycosides
`7.4 Antidepressant Ther
`apy
`7.5 Ketamine
`7.6 Sympathomimetics
`7.7 Drug-Laboratory Test Interactions
`8 USES IN SPECIFIC POPUL
`ATIONS
`8.1 Pregnancy
`8.2 Labor and Deliver
`y
`
`8.3 Nursing Mothers
`
`
`
`
`5.2
`
`
`
`Reference ID: 2965603
`
`jection
`
`OR
`
`se caution
`
`

`

`
`
`
`
`
`FULL PRESCRIBI
`
`NG INFORMATION
`
`1
`
`INDICATI
`
`ONS AND USAGE
`
`Levothyroxine Sodium for Injection is indicated for the treatment of myxedema coma.
`
`
`Important Limitations of Use: The relative bioavailability between Levothyroxine Sodium
`
`for Injection and oral levothyroxine products has not been established. Caution should be
`
`thyroxine Sodium for
`used when switching patients from oral levothyroxine products to Levo
`
`een studied.
`Injection as accurate dosing conversion has not b
`
`2
`
`DOSAGE AND ADM
`
`INISTRATION
`
`2.1
`
`Dosage
`
`An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to
`
`500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg,
`
`should be administered, as clinically indicated, until the patient can tolerate oral therapy.
`
`The age, general physical condition, cardiac risk factors, and clinical severity of myxedema
`
`
`
`ining the starting
`and duration of myxedema symptoms should be considered when determ
`
`and maintenance dosages of Levothyroxine Sodium for Injection.
`
`Levothyroxine Sodium for Injection produces a gradual increase in the circulating
`
`concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid
`
`patients. Daily administration of Levothyroxine Sodium for Injection should be maintained
`
`ic
`until the patient is capable of tolerating an oral dose and is clinically stable. For chron
`
`treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to
`
`maintain a euthyroid state. Relative bioavailability between Levothyroxine Sodium for
`
`Injection and oral levothyroxine products has not been established. Based on medical
`
`practice, the relative bioavailability between oral and intravenous administration of
`
`
`
`Reference ID: 2965603
`
`2
`
`

`

`
`
`Levothyroxine Sodium for Injection is estimated to be from 48 to 74%. Due to difference
`
`s
`
`
`
`in absorption characteristics of patients and the oral levothyroxine product formulations,
`
`TSH and thyroid hormone levels should be me
`
`asured a few weeks after initiating oral
`
`levothyroxine and dose adjusted accordingly.
`
`2.2
`
`Dosing in the Elderly and in Patients with Cardiovascular Disease
`
`Intravenous levothyroxine may be associated with cardiac toxicity-including arrhythmias,
`
`tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure
`
`and death—in the elderly and in those with underlying cardiovascular disease. Therefore,
`
`cautious use, includin
`
`g doses in the lower end of the recommended range, may be warranted
`
`in these populations.
`
`2.3
`
`Reconstitution Directions
`
`
`Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL
`
`of 0.9% Sodium Chloride Injection, USP only. Shake vial to ensure complete mixing. The
`
`resultant solution will have a final concentration of approximately 20 mcg per mL, 40 mcg
`
`per mL and 100 mcg per mL for the 100 mcg, 200 mcg and 500 mcg vials, respectively.
`
`
`
`n.
`Reconstituted drug product is preservative free. Use immediately after reconstitutio
`
`Discard any unused portion. DO NOT ADD LEVOTHYROXINE SODIUM FOR
`
`INJECTION TO OTHER IV FLUIDS. Parenteral drug products should be inspected
`
`visually for particulate
`
` matter and discoloration prior to administration, whenever solution
`
`and container permit.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`wder at three strengths in
`Levothyroxine Sodium for Injection is supplied as a lyophilized po
`
`single use amber-colored via
`
`ls: 100 mcg, 200 mcg and 500 mcg.
`
`4
`
`CONT
`
`RAINDICATIONS
`
`
`
`Reference ID: 2965603
`
`3
`
`

`

`
`
`None
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`
`Risk of Cardiac Complications in Elderly and in Patients with Cardiovascular Disease
`
`e
`Excessive bolus dosing of Levothyroxine Sodium for Injection (greater than 500 mcg) ar
`
`h an
`associated with cardiac complications, particularly in the elderly and in patients wit
`
`underlying cardiac condition. Adverse events that can potentially be related to the
`
`administration of large doses of Levothyroxine Sodium for Injection include arrhythmias,
`
`tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure
`
`ge, may
`and death. Cautious use, including doses in the lower end of the recommended ran
`
` following the
`be warranted in these populations. Close observation of the patient
`
`administration of Levothyroxine Sodium for Injection is advised.
`
`5.2
`
`cocorticoids and Monitoring for Other Diseases in Patients
`Need for Concomitant Glu
`
`with Endocrine Disorders
`
`Occasionally, chronic autoimmune thyroiditis, which can lead to myxedema coma, m
`
`ay
`
`occur in association with other autoimmune disorders such as adrenal insufficiency,
`
`pernicious anemia, and insulin-dependent diabetes mellitus. Patients should be treated with
`
`m for
`replacement glucocorticoids prior to initiation of treatment with Levothyroxine Sodiu
`
`Injection, until adrenal function has been adequately assessed. Failure to do so may
`
`precipitate an acute adrenal crisis when thyroid hormone therapy is initiated, due to
`
`increased metabolic clearance of glucocorticoids by thyroid hormone. With initiatio
`
`n of
`
`a should also be
`Levothyroxine Sodium for Injection, patients with myxedema com
`
`etes insipidus.
`monitored for previously undiagnosed diab
`
`5.3
`
`Not Indicated for Treatment of Obesity
`
`
`
`Reference ID: 2965603
`
`4
`
`

`

`
`
`Thyroid hormones, including Levothyroxine Sodium for Injection, either alone or with other
`
`therapeutic agents, should not be used for the treatment of obesity or for weight loss. In
`
`
`
`euthyroid patients, doses within the range of daily hormonal requirements are ineffective for
`
`
`
`weight reduction. Larger doses may produce serious or even life threatening manifestations
`
`of toxicity, particularly when give
`
`n in association with sympathomimetic amines such as
`
`those used for their anorectic effects. [See Adverse Reactions (6) and Overdosage (10)]
`
`6
`
`ADVERSE REACTIONS
`
`Excessive doses of levothyroxine can predispose to signs and symptoms compatible with
`
`hyperthyroidism. The signs and symptoms of thyrotoxicosis include, but are not limite
`
`d to:
`
`,
`exophthalmic goiter, weight loss, increased appetite, palpitations, nervousness, diarrhea
`
`ps, sweating, tachycardia, increased pulse and blood pressure, cardiac
`abdominal cram
`
`ors, insomnia, heat intolerance, fever, and menstrual
`arrhythmias, angina pectoris, trem
`
`irregularities.
`
`7
`
`DRUG INTERACTIONS
`
`Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., synthesis,
`
`secretion, catabolism, protein binding, and target tissue response) and may alter the
`
`therapeutic response
`
`to Levothyroxine Sodium for Injection. In addition, thyroid hormones
`
`and thyroid status have varie
`
`d effects on the pharmacokinetics and actions of other drugs
`
`(See Section 12.3).
`
`7.1
`
`Antidiabetic Therapy
`
`Addition of levothyroxine to antidiabetic or insulin therapy may result in increased
`
`ulin requirements. Careful monitoring of diabetic control is
`antidiabetic agent or ins
`
`recommended, especially when thyroid therapy is started, changed, or discontinued.
`
`7.2
`
`Oral Anticoagulants
`
`
`
`Reference ID: 2965603
`
`5
`
`

`

`
`
`Levothyroxine increases the response to oral anticoagulant therapy. Therefore, a decreas
`
`e in
`
`the dose of anticoagulant may be warranted with correction of the hypoth
`
`yroid state or when
`
` for Injection dose is increased. Prothrombin time should be
`the Levothyroxine Sodium
`
`closely monitored to permit appropriate and timely dosage adjustments.
`
`7.3
`
`Digitalis Glycosides
`
`The therapeutic effects of digitalis glycosides may be reduce
`
`d by levothyroxine. Serum
`
`digitalis glycoside levels may b
`
`e decreased when a hypothyroid patient becomes euthyroid,
`
`necessitating an increase in the dose of digitalis glycosides.
`
`7.4
`
`Antidepressant Therapy
`
`Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline)
`
`h
`antidepressants and levothyroxine may increase the therapeutic and toxic effects of bot
`
`drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effect
`
`s may
`
`onset of action of
`include increased risk of cardiac arrhythmias and CNS stimulation;
`
`e accelerated. Administration of sertraline in patients stabilized on
`tricyclics may b
`
`levothyroxine may result in increased levothyroxine requirements.
`
`7.5
`
`Ketamine
`
`Concurrent use may prod
`
`uce marked hypertension and tachycardia; cautious administration
`
`to patients receiving thyroid hormone therapy is recommended.
`
`7.6
`
`Sympathomimetics
`
`imetics or thyroid hormone. Thyroid
`Concurrent use may increase the effects of sympathom
`
`hormones may increase the risk of coronar
`
`y insufficiency when sympathomimetic agents are
`
`administered to patients with coronary artery disease.
`
`7.7
`
`Drug-Laboratory Test Interactions
`
`
`
`Reference ID: 2965603
`
`6
`
`

`

`
`
`Changes in thyroxine binding globulin (TBG) concentration must be considered when
`
`interpreting levothyroxine and triiodothyronine values, which necessitates measurement and
`
`
`
`evaluation of unbound (free) hormone and/or determination of the free levothyroxine index.
`
`
`
`Pregnancy, infectious hepatitis, estrogens, estrogen containing oral contraceptives, and acute
`
`
`
`intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are
`
`observed in nephrosis, severe hypoprotein
`
`emia, severe liver disease, acromegaly, and after
`
`androgen or cort
`
`icosteroid therapy. Familial hyper or hypo thyroxine binding globulinemias
`
`have been described, with the incidence of TBG deficiency approximating 1 in 9000.
`
`8
`
`USES IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Pregnancy Category A – There are no reported cases of Levothyroxine Sodium for
`
`s
`Injection used to treat myxedema coma in patients who were pregnant or lactating. Studie
`
`in pregnant women treated with oral levothyroxine to maintain a euthyroid state have not
`
`shown an increased risk of fetal
`
` abnormalities. Therefore, pregnant patients who develop
`
`myxedema should be treat
`
`ed with Levothyroxine Sodium for Injection as the risk of non-
`
`treatment is associated with a high probability of significant morbidity or mortality to the
`
`maternal patient and the fetus.
`
`8.2
`
`Labor and Delivery
`
`yxedema have not been reported in the literature. However,
`Patients in labor who develop m
`
`ed with Levothyroxine Sodium for Injection as the risk of non-
`patients should be treat
`
`treatment is associated with a high probability of significant morbidity or mortality to the
`
`maternal patient and the fetus.
`
`8.3
`
`Nursing Mothers
`
`
`
`Reference ID: 2965603
`
`7
`
`

`

`
`
`
`
`Adequate replacement doses of thyroid hormones are required to maintain normal lactation.
`
`
`
`There are no reported cases of Levothyroxine Sodium for Injection used to treat myxedema
`
`coma in patients wh
`
`o are lactating. However, such patients should be treated with
`
`Levothyroxine Sodium for Injection as the risk of nontreatment is associated wit
`
`h a high
`
`probability of significant morbidity or mortality to the nursing patient.
`
`8.4
`
`Pediatric Use
`
`Myxedema coma is a disease of the elderly. An approved, oral dosage fo
`
`rm of
`
`
`levothyroxine should be used in the pediatric patient population for maintaining a euthyroid
`
`state in non-complicated hypothyroidism.
`
`8.5
`
`Geriatric Use and Patients with Underlying Cardiovascular Disease
`
`See Section 2, Dosage and Administration, for full prescribing information in the geria
`
`tric
`
`patient population. Because of the increased prevalence of cardiovascular disease in the
`
`elderly, cautious use of Levothyroxin
`
`e Sodium for Injection in the elderly and in patients
`
`. Atrial fibrillation is a common side effect
`with known cardiac risk factors is advised
`
`associated with levothyroxin
`
`e treatment in the elderly. [See Dosage and Administration (2)
`
`d Precautions (5)]
`and Warnings an
`
`9
`
`DRUG AB
`
`USE AND DEPENDENCE
`
`9.1
`
`stance
`Controlled Sub
`
`Not applicable.
`
`9.2
`
`Abuse
`
`Not applicable.
`
`9.3
`
`Dependence
`
`Not applicable.
`
`10
`
`OVERDOSAGE
`
`
`
`Reference ID: 2965603
`
`8
`
`

`

`
`
`In general, the signs and symptoms of overdosage with levothyroxine are those of
`
`hyperthyroidism. [See Warnings and Precautions (5) and Adverse Reactions (6)] In
`
`addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and
`
`death have been reported. E
`
`xcessive doses of Levothyroxine Sodium for Injection (greater
`
`than 500 mcg) are associated with cardiac complications in patients with underlying cardiac
`
`disease.
`
`Treatment of Overdosage
`
`Levothyroxine Sodium for Injection should be reduced in dose or temporarily discontin
`ued
`
`if signs or symptoms of overdosage occur. To obtain u
`
`p-to-date information about the
`
`treatment of overdose, a good resource is the certified Regional Poison Control Center. In
`
`managing overdosage, consider
`the possibility of multiple drug overdoses, interaction
`
`among drugs, and
`
`unusual drug kinetics in the patient.
`
`In the event of an overdose, appropriate supportive treatment should be initiated as d
`
`ictated
`
`by the patient’s medical status.
`
` 11
`
`DESCRIPTION
`
`Levothyroxine Sodium for Injection contains synthetic crystalline levothyroxine (L-
`
`thyroxine) sodium salt. Levothyroxine sodium has an empirical formula of C15H10I4NNaO4,
`
`a molecular weight of 798.85 g/mol (anhydrous), and the following structural formula:
`
`
`
`Levothyroxine Sodium for Injection is a sterile, preservative-free lyophilized powde
`
`r
`
`consisting of the active ingredient, levothyroxine sodium, and the exc
`
`ipients dibasic sodium
`
`phosphate heptahydrate, USP; mannitol,
`
`USP; and sodium hydroxide, NF in single-use
`
`
`
`Reference ID: 2965603
`
`9
`
`

`

`
`
`amber glass vials. Levothyroxine Sodium for Injection is available at three dosage
`
`strengths: 100 mcg per vial, 200 mcg per vial and 500 mcg per vial.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1
`
`Mechanism of Action
`
`
`
`nd Thyroid hormones exert their physiologic actions through control of DNA transcription a
`
`protein sy
`
`nthesis. Triiodothyronine (T3) and levothyroxine (T4) diffuse into the cell nucleus
`
`and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor
`
`complex activates gene transcription and synthesis of messenger RNA and cytoplasmic
`
`proteins.
`
`
`
`The physiological action
`
`s of thyroid hormones are produced predominantly by T3, the
`
`majority of which (approximately 80%) is derived from T4 by deiodination in peripheral
`
`tissues.
`
`12.2
`
`Pharmacodynamics
`
`Thyroid hormone synthesis and secretion is regulated by the hypothalamic pituitary-thyroid
`
`axis. Thyrotropin releasing hormone (TRH) released from the hypothalamus stimulates
`
`secretion of thyrotropin stimulating hormone (TSH) from the anterior pituitary. TSH, in
`
`turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, T4 and
`
`T3, by the thyroid gland. Circulating serum T3 and T4 levels exert a feedback effect o
`n both
`
`TRH and TSH secretion. When serum T3 and T4 levels increase, TRH and TSH secretion
`
`decrease. When thyroid hormone levels decrease, TRH and TSH secretion increases.
` TSH
`
`is used for the diagnosis of hypothyroidism and evaluation of levothyroxine therapy
`
`adequacy with other laboratory and clinical data. [See Dosage (2.1)] There are drugs know
`n
`
`to affect thyroid hormones and TSH by various mechanisms and those examples are
`
`diazepam, ethioamide, lovastatin, metoclopramide, 6-mercaptopurine, nitroprusside,
`
`
`
`Reference ID: 2965603
`
`10
`
`

`

`
`
`perphenazine, and thiazide diuretics. Some drugs may cause a transient decrease in TSH
`
`secretion without hypothyroidism and those drugs (dose) are dopamine (greater than 1 mcg
`
`per kg per min), glucocorticoids (hydrocortisone greater than 100 mg per day or equiva
`
`lent)
`
`and octreotide (greater than 100 mcg per day).
`
`Thyroid hormones regulate multiple metabolic processes and play an essential role i
`
`n
`
`normal growth and development, and normal maturation of the central nervous system and
`
`bone. The metabolic actions of thyroid hormones include augmentation of cellular
`
`respiration and
`
` thermogenesis, as well as metabolism of proteins, carbohydrates and lipids.
`
`The protein anabolic ef
`
`fects of thyroid hormones are essential to normal growth and
`
`development.
`
`12.3
`
`Pharmacokinetics
`
`Absorption – Levothyroxine Sodium for Injectio
`n is administered via the intravenous route.
`
`Following administration, the synthetic levothyroxine cannot be distinguished from the
`
`natural hormone that is secreted endogenously.
`
`Distribution – Circulating thyroid hormones are greater than 99% bound to plasma proteins
`,
`
`including 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 T4 partially explains the higher serum levels, slower metabo
`lic
`
`clearance, and longer half life of T4 compared to T3. 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. [See Warning
`
`s and Precautions (5) and Drug Interactions (7)]
`
`Thyroid hormones do not readily cross the placental barrier. [See Warnings and Precautions
`
`(5) and Uses in Specific Populations (8)]
`
`
`
`Reference ID: 2965603
`
`11
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`

`
`
`
`
`
`
`Metabolism – T4 is slowly eliminated. The major pathway of thyroid hormone metabolism
`
`is through sequential deiodination. Approximately eighty percent of circulating T3 is
`
`derived from peripheral T4 by monodeiodination. The liver is the major site of degrad
`ation
`
`for both T4 and T3, with T4 deiodination also occurring at a number of additional sites,
`
`including the kidney and other tissues. Approximately 80% of the daily dose of T4 is
`
`deiodinated to yield equal amounts of T3 and reverse T3 (r T3). T3 and r T3 are further
`
`
`
`deiodinated to diiodothyronine. Thyr
`oid hormones are also metabolized via conjugation
`
`with glucuronides and sulfates and excreted directly into the bile and gut where they
`
`undergo enterohepatic recirculation.
`
`Elimination – Thyroid hormones are primarily eliminated by the kidneys
`. A portion of the
`
`conjugated hormone reaches the colon unchanged, where it is hydrolyzed and eliminated in
`
`feces as the free hor
`
`mones.
` Urinary excretion of T4
`
` decreas
`
`es with age.
`
`Table
`
`1: P
`harmacokinetic Param rs of
`ete
`
`id Ho
` Thyro
`
`es in Euthyroid Patients
`rmon
`
`Ratio in
`Hormone Thyroglobulin
`10 – 20
`T4
`1
`T
`3
`T4: Levothyroxine
`
`T3: Liothyronine
`
`Biologic
`Potency
`1
`4
`
`Half-
`Life
`(Days)
`6 – 81
`≤ 2
`
`Protein
`Binding
`(%)2
`99.96
`99.5
`
`1 3 – 4 days in hyperthyroidism, 9 – 10 days in hypothyroidism.
`
`2 Includes TBG, TBPA, and TBA.
`
`Drug Interactions
`
`A listing of drug interaction with T4 is provided in the following tables, although it may not
`
`l axis
`be comprehensive due to the introduction of new drugs that interact with the thyroida
`
`or the discovery of previously unknown interactions. The prescriber should be aware of this
`
`opriate reference sources (e.g., package inserts of newly
`fact and should consult appr
`
`12
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`Reference ID: 2965603
`
`

`

`approved drugs, medical literature) for additional information if a drug-drug interaction
`
` with
`
`levothyroxine is suspected.
`
`
`
`Table 2: Drugs That May Alter T4 and T3 Serum Transpor
`
`t Without Affecting free T4
`
`Concentration (Euthyroidism)
`
`Drugs That May Decrease
`
`Serum TBG Concentration
`Androgens / Anabolic Steroids
`Asparaginase
`Glucocorticoids
`Slow-Release Nicotinic Acid
`
`EH
`
`Drugs That May
` Increase
`
`tration Serum TBG Concen
`Clofibrate
`Estrogen-co
`ntaining oral
`
`contraceptives
`rogens (oral)
`st
`eroin / Methadone
`5-Fluorouracil
`Mitotane
`Tamoxifen
`Drugs That May Cause Protein-Binding Site Displacement
`
`
`Potential impact: Administration
`of these agents with levothyroxin
`e
`in FT4. Continued
`results
`in an
`initial
`transien
`t
`
`increase
`e in serum T and normal FT4 and 4
`administration results in a decreas
`
`, patients are clinically euthyro
`TSH concentrations and, therefore
`id.
`
`Salicylates (> 2 g/day)
`
`Salicylates inhibit binding of T4
`and T3 to TBG and transthyretin.
`An initial increase in serum FT4 i
`s
`by return of FT4 to
`followed
`ormal levels with sustained
`n
`therapeutic serum salicylate
`concentrations, although total-T4
`levels may decrease by as much
`as 30%.
`
`
`> 80 mg IV)
`
`Other drugs:
`
`Furosemide (
`Heparin
`Hydantoins
`Non-Steroidal Anti-inflammatory
`Drugs
`- Fenamates
`- Phenylbutazone
`
`
`
`Table 3: Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
`
`Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may
`
`cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine
`
`
`
`requirements.
`
`Drug or Drug Class
`Carbamazepine
`Hydantoins
`
`
`Phenytoin and carbamazepine
` of
`reduce serum protein binding
`vothyroxine, and total- and free-
`le
`T4 may be reduced by 20% to
`
`13
`
`
`
`
`
`Reference ID: 2965603
`
`

`

`
`
`Other drugs:
`Phenobarbital
`Rifampin
`
`
`
`40%, but most patients have
`normal serum TSH levels and are
`clinically euthyroid.
`
`
`Table 4: Drugs That May Decrease Conversion of T4 to T3
`
`Potential impact: Administration of these enzyme inhibitors decreases the peripheral
`
`conversion o
`
`f T4 to T3, leadin
`
`g to decreased
`
`
`
`els. However, serum T4 levels are usually T3 lev
`
`normal
`
`
`
`s but may occasionally be lightly increased.
`
`Drug or Drug Class
`Beta-adrenergic antagonists
`(e.g. Propranolol > 160 mg/day)
`
`Glucocorticoids
`(e.g. Dexamethasone > 4 mg/day)
`
`
`Effect
`In patients treated with large
`doses of propranolol (> 16
`0
`mg/day), T3 and T4 levels chang
`e
`slightly, TSH levels remain
`nically
`normal, and patients are cli
`ld be noted that
`euthyroid. It shou
`actions of particular beta-
`adrenergic antagonists may be
`impaired when the hypothyroid
`patient is converted to the
`euthyroid state.
`Short-term administration of large
`doses of glucocorticoids may
`
`decrease serum T3 concentrations
` in
`by 30% with minimal change
`serum T4 levels. However, long-
`rm glucocorticoid therapy may
`te
`result in slightly decreased T3 and
`T4 levels due to decreased TBG
`production (See above).
`
`Other drug:
`Amiodarone
`
`
`
`
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`o evaluate the carcinogenic potential, mutagenic Animal studies have not been performed t
`
`potential or effects on fertility of Levothyroxine Sodium for Injection.
`
`13.2
`
`
`
`xicology and Pharmacology Animal To
`
`No animal toxicology studies
` have been conducted with Levothyroxine Sodium for
`
`Injection.
`
`
`
`Reference ID: 2965603
`
`14
`
`

`

`
`
`14
`
`CLINICAL STUDIES
`
`No clinical studies have been conducted with Levothyroxine Sodium for Injection in
`
` the
`patients with myxedema coma. However, data from published literature support
`
`thyroxine sodium for the treatment of myxedema coma.
`intravenous use of levo
`
`15
`
`
`REFERENCES
`
`Not applicable.
`
`16
`
`HOW SUPPLIED
`
`/STORAGE AND HANDLING
`
`16.1
`
`How Supplied
`
`Levothyroxine Sodium for
` Injection is ava
`
`ilable in three dosage strengths.
`
`Strength
`
`Reconstituted
`
`Concentration
`
`100 mcg/vial
`
`20 mcg/mL
`
`200 mcg/vial
`
`40 mcg/mL
`
`500 mcg/vial
`
`100 mcg/mL
`
`Product No.
`
`NDC No.
`
`506107
`
`24710
`
`24810
`
`63323-506-10
`
`63323-247-10
`
`63323-248-10
`
`
`
`16.2
`
`Storage and Handling
`
`Protect from light and store dry product at 20° to 25°C (68° to 77°F) [see USP Controlled
`
`Room Te
`
`mperature]. Reconstituted drug product is preservative free. Discard any unused
`
`portion.
`
`17
`
`NSELING INFORMATION
`PATIENT COU
`
`Not applicable.
`
`
`45804D/Revised: June 2011
`
`
`
`Reference ID: 2965603
`
`15
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`06/24/2011
`
`Reference ID: 2965603
`
`