---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Lyophiliz ed powder for injection in single use vials: 100 mcg, 200 mcg, 500
`mcg. (3)
`
`
`
`
`•
`
`
`•
`
`
`------------------------------CONTRAINDICATIONS-------------------------------
`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 tration of
`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
`compatible with hyperthyroidism.
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact APP
`
`Pharmaceuticals, LLC, Medical Affairs Department at 1-800-551-7176 or
`
`
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------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 should
`
`•
`receive doses at the lower end of the recommended range. (8.5)
`
`
`
`
`
`_________________________________________________
`___________________________
`__________________
`_________________________________________
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`Levothyroxine Sodium for Injection safely and effectively. See full
`
`
`prescribing information for Levothyr oxine Sodium for Injection.
`
`Levothyroxine Sodium for In jection
`Initial U.S. Approval: 1969
`
`
`
`WARNING: NOT FOR TREATMENT OF OBESITY OR F OR
`
`
`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 se caution
`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)
`Do not add to other IV fluids. (2.3)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosage
`
`2.2 Dosing in the Elderly and in Patient s with Cardiovascular Disease
`
`
`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
`
`5.2 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
`
`
`
`
`
`
`Reference ID: 2965603
`
`
`
`
`
`
`
`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
`12 CLINICAL PHARMACOLO GY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairme nt of Fertility
`
`13.2 Animal Toxicology and Pharmacology
`
`
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`

`

`
`
`
`
`
`FULL PRESCRIBI NG INFORMATION
`
`1
`
`INDICATIONS 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
`
`used when switching patients from oral levothyroxine products to Levo thyroxine Sodium for
`
`
`Injection as accurate dosing conversion has not b een studied.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`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
`
`and duration of myxedema symptoms should be considered when determ ining the starting
`
`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
`
`until the patient is capable of tolerating an oral dose and is clinically stable. For chronic
`
`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 differences
`
`in absorption characteristics of patients and the oral levothyroxine product formulation s,
`
`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,
`
`
`
`g doses in the lower end of the recommended range, may be warranted cautious use, includin
`
`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
`
`
`
` matter and discoloration prior to administration, whenever solution visually for particulate
`
`and container permit.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`wder at three strengths inLevothyroxine Sodium for Injection is supplied as a lyophilized po
`
`
`
`ls: 100 mcg, 200 mcg and 500 mcg. single use amber-colored via
`
`
`
`RAINDICATIONSCONT
`
`4
`
`
`
`3
`
`
`Reference ID: 2965603
`
`
`

`

`
`
`None
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`
`Risk of Cardiac Complications in Elderly and in Patients with Cardiovascular Disease
`
`Excessive bolus dosing of Levothyroxine Sodium for Injection (greater than 500 mcg) ar e
`
`associated with cardiac complications, particularly in the elderly and in patients wit h an
`
`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
`
`and death. Cautious use, including doses in the lower end of the recommended ran ge, may
`
`be warranted in these populations. Close observation of the patient following the
`
`administration of Levothyroxine Sodium for Injection is advised.
`
`5.2
`
`Need for Concomitant Glucocorticoids and Monitoring for Other Diseases in Patients
`
`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
`
`replacement glucocorticoids prior to initiation of treatment with Levothyroxine Sodiu m for
`
`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
`
`Levothyroxine Sodium for Injection, patients with myxedema com a should also be
`
`monitored for previously undiagnosed diabetes insipidus.
`
`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 f or
`
`weight reduction. Larger doses may produce serious or even life threatening manifestati ons
`
`
`
`n in association with sympathomimetic amines such as of toxicity, particularly when give
`
`
`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
`
`
`
`d to:hyperthyroidism. The signs and symptoms of thyrotoxicosis include, but are not limite
`
`
`
`,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
`
`
`
`d effects on the pharmacokinetics and actions of other drugs and thyroid status have varie
`
`(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 decrease in
`
`the dose of anticoagulant may be warranted with correction of the hypoth yroid state or when
`
`the Levothyroxine Sodium for Injection dose is increased. Prothrombin time should be
`
`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)
`
`antidepressants and levothyroxine may increase the therapeutic and toxic effects of bot h
`
`drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effect s may
`
`include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of
`
`tricyclics may be accelerated. Administration of sertraline in patients stabilized on
`
`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
`
`Concurrent use may increase the effects of sympathom imetics or thyroid hormone. Thyroid
`
`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 hypoproteinemia, severe liver disease, acromegaly, and after
`
`androgen or corticosteroid 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
`
`Injection used to treat myxedema coma in patients who were pregnant or lactating. Studies
`
`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
`
`Patients in labor who develop myxedema have not been reported in the literature. However,
`
`patients should be treated 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.
`
`8.3
`
` Nursing Mothers
`
`
`
`Reference ID: 2965603
`
`7
`
`
`

`

`
`
`Adequate replacement doses of thyroid hormones are required to maintain normal lactatio n.
`
`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 form 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 Levothyroxine Sodium for Injection in the elderly and in patients
`
`with known cardiac risk factors is advised . Atrial fibrillation is a common side effect
`
`
`associated with levothyroxin e treatment in the elderly. [See Dosage and Administration (2)
`
`and Warnings and Precautions (5)]
`
`
`9
`
`DRUG ABUSE AND DEPENDENCE
`
`9.1
`
`Controlled Sub stance
`
`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. Excessive 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 up-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
`
`9
`
`
`Reference ID: 2965603
`
`

`

`
`
`
`
` 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
`
`Thyroid hormones exert their physiologic actions through control of DNA transcription a nd
`
`protein synthesis. 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 actions 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 on 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 known
`
`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 effects of thyroid hormones are essential to normal growth and
`
`development.
`
`12.3
`
` Pharmacokinetics
`
`Absorption – Levothyroxine Sodium for Injection 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 Warnings 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
`
`
`

`

`
`
`
`
`
`
`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. Thyroid 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 hormones. Urinary excretion of T4 decreases with age.
`
`
`Table 1: Pharmacokinetic Param eters of Thyro id Hormon es in Euthyroid Patients
`
`Ratio in
` Hormone Thyroglobulin
`
`
`10 – 20
` T4
`1
`T3
`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
`
`be comprehensive due to the introduction of new drugs that interact with the thyroida l axis
`
`or the discovery of previously unknown interactions. The prescriber should be aware of this
`
`fact and should consult appropriate reference sources (e.g., package inserts of newly
`
`12
`
`
`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 Transport Without Affecting free T4
`
`
`Concentration (Euthyroidism)
`
`
` Drugs That May Decrease
`
` Serum TBG Concentration
`Androgens / Anabolic Steroids
`Asparaginase
`Glucocorticoids
`
`Slow-Release Nicotinic Acid
`
` Increase Drugs That May
`
`
`
`Serum TBG Concen tration
`
`Clofibrate
`
`Estrogen-co ntaining oral
`contraceptiv
`es
`
`
`st rogens (oral)E
`
`Heroin / 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
`t
`increase
`transien
`results
`in an
`initial
`
`e in serum T and normal FT4 and4
`administration results in a decreas
`
`
`
`, patients are clinically euthyro
`id.
`TSH concentrations and, therefore
`
`
`
`
`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%.
`
`
`Other drugs:
`
`
`Furosemide ( > 80 mg IV)
`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 free­le
`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 of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually
`
`
`
`normal but may occasionally be lightly increased. s
`
`
`
`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
`
`
`te rm glucocorticoid therapy may
`
`
` 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
`
`Animal studies have not been performed t o evaluate the carcinogenic potential, mutagenic
`
`potential or effects on fertility of Levothyroxine Sodium for Injection.
`
`13.2 Animal Toxicology and Pharmacology
`
`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
`
`patients with myxedema coma. However, data from published literature support the
`
`
`intravenous use of levothyroxine sodium for the treatment of myxedema coma.
`
`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
`
` PATIENT COU NSELING INFORMATION
`
`Not applicable.
`
`
`
`
`45804D/Revised: June 2011
`
`
`
`Reference ID: 2965603
`
`15
`
`
`
`