LEVOTHYROXINE SODIUM-levothyroxine sodium anhydrous injection, powder, lyophilized,
`for solution
`Fresenius Kabi USA, LLC
`
`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 Levothyroxine Sodium for Injection.
`
`Levothyroxine Sodium for Injection
`Initial U.S. Approval: 1969
`
`WARNING: NOT FOR TREAT MENT OF OBESITY OR FOR WEIGHT LOSS
`
`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)
`
`wrnr nn ne nnn ene e een eeeee INDICATIONS AND USAGE ----------------------------------0--------
`
`Levothyroxine Sodiumis an L-thyroxine product. Levothyroxine (T,) Sodium for Injection is indicated for the treatment of
`myxedema coma.(1)
`Important Limitations of Use:
`The relative bioavailability of this drug has not been established. Use caution when converting patients from oral to
`intravenous levothyroxine.
`want ene enn n eee e eee nenee nee eeeneee DOSAGE AND ADMINISTRATION -----------------------------------+---
`
`®
`
`Aninitial 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)
`e Reconstitute the lyophilized Levothyroxine Sodiumfor 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)
`
`wn een nee en nee e ene een eeeeeeneeeeneee DOSAGE FORMS AND STRENGTHS ---------------------------------------
`Lyophilized powder for injection in single use vials: 100 mcg, 200 mcg and 500 mcg. (3)
`wee eee eee e ene n en en ene nnnens CONTRAINDICATIONS-------------- +--+ ++ 2-22-2222 2e eee eee e ee eee
`None. (4)
`wnnn ee ees WARNINGS AND PRECAUTIONS-----------------------------+-----------
`
`e 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)
`e Close observation of the patient following the administration of Levothyroxine Sodium for Injection is advised. (5.1)
`e Levothyroxine Sodium for Injection therapy for patients with previously undiagnosed endocrine disorders, including
`adrenalinsufficiency, hypopituitarism, and diabetes insipidus, may worsen symptoms of these endocrinopathies. (5.2)
`
`mr araccaracraraccseanccrssncranccraaccraaccns ADVERSE REACTIONS---------------------------------------------
`
`Excessive doses of L-thyroxine can predispose to signs and symptoms compatible with hyperthyroidism. (6)
`(6)
`To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Medical Affairs Department
`at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.(6)
`teh nie ee oe eee eee DRUG INTERACTIONS---------------------------------------------
`Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism,
`protein binding, and target tissue response) and mayalter the therapeutic response to Levothyroxine Sodium for Injection.
`(7, 12.3)
`eee eee eee eee nena eee USEIN SPECIFIC POPULATIONS-------------+-+-++---2--+-2--+----005-
`
`e Elderly and those with underlying cardiovascular disease should receive doses at the lower end of the recommended
`range. (8.5)
`
`Revised: 12/2013
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: NOT FOR TREATMENTOF OBESITY OR FOR WEIGHT LOSS
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosage
`2.2 Dosing inthe Elderly and in Patients with Cardiovascular Disease
`2.3 Reconstitution Directions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Cardiac Complications in Elderly and in Patients with Cardiovascular Disease
`5.2 Need for Concomitant Glucocorticoids and Monitoring for Other Diseases in Patients with
`Endocrine Disorders
`5.3 Not Indicated for Treatment of Obesity
`6 ADVERSE REACTIONS
`7 DRUG INTERACTIONS
`7.1 Antidiabetic Therapy
`7.2 Oral Anticoagulants
`7.3 Digitalis Glycosides
`7.4 Antidepressant Therapy
`7.5 Ketamine
`7.6 Sympathomimetics
`7.7 Drug-Laboratory TestInteractions
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use and Patients with Underlying Cardiovascular Disease
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and Pharmacology
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`* Sections or subsections omitted from the full prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`
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`Larger doses may produce serious or even life threatening manifestations of toxicity. (6)
`
`WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
`Thyroid hormones, including Levothyroxine Sodium for Injection, should not be used for
`the treatmentof obesity or for weightloss. (5.3)
`
`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 Levothyroxine Sodium for Injection as accurate dosing conversion has
`not been 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 determining 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 andis clinically stable. For chronic treatment of hypothyroidism, an oral dosage formof
`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
`Levothyroxine Sodium for Injection is estimated to be from48 to 74%. Dueto differences in
`absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid
`hormone levels should be measured 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, including doses inthe
`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 and 100 mcg per mL
`for the 100 mcg, 200 mcg and 500 mcg vials, respectively. Reconstituted drug productis preservative
`free and is stable for 4 hours. 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
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`permit.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Levothyroxine Sodium for Injection is supplied as a lyophilized powder at three strengths in single use
`amber-colored vials: 100 mcg, 200 mcg and 500 mcg.
`
`4 CONTRAINDICATIONS
`
`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) are associated
`with cardiac complications, particularly in the elderly and in patients with 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 heartfailure and death. Cautious use, including doses in the
`lower end of the recommended range, 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, may occurin
`association with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and
`insulinidependent diabetes mellitus. Patients should be treated with replacement glucocorticoids prior
`to initiation of treatment with Levothyroxine Sodium 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
`initiation of Levothyroxine Sodium for Injection, patients with myxedema coma should also be
`monitored for previously undiagnosed diabetes insipidus.
`
`5.3 Not Indicated for Treatmentof Obesity
`
`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 weightloss. 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
`given 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 limited to:
`exophthalmic goiter, weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal
`cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, angina
`pectoris, tremors, insomnia, heat intolerance, fever, and menstrual irregularities.
`
`7 DRUG INTERACTIONS
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`Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., synthesis, secretion,
`catabolism, protein binding, and target tissue response) and mayalter the therapeutic response to
`Levothyroxine Sodium for Injection. In addition, thyroid hormones and thyroid status have varied
`effects onthe pharmacokinetics and actions of other drugs (see Section 12.3).
`
`7.1 Antidiabetic Therapy
`
`Addition of levothyroxine to antidiabetic or insulin therapy may result inincreased antidiabetic agent or
`insulinrequirements. Careful monitoring of diabetic control is recommended, especially when thyroid
`therapy is started, changed, or discontinued.
`
`7.2 Oral Anticoagulants
`
`Levothyroxine increases the response to oral anticoagulant therapy. Therefore, a decrease inthe dose
`of anticoagulant may be warranted with correction of the hypothyroid 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 reduced by levothyroxine. Serum digitalis
`glycoside levels may be decreased whenahypothyroid 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 both drugs, possibly due to increased
`receptor sensitivity to catecholamines. Toxic effects 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 produce marked hypertension and tachycardia; cautious administration to patients
`receiving thyroid hormone therapy is recommended.
`
`7.6 Sympathomimetics
`
`Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones
`may increase the risk of coronary insufficiency when sympathomimetic agents are administered to
`patients with coronaryartery disease.
`
`7.7 Drug-Laboratory Test Interactions
`
`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 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
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`Pregnancy Category A — Thereare 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 shownan increased risk of fetal abnormalities.
`Therefore, pregnant patients who develop myxedema should be treated with Levothyroxine Sodium for
`Injection as the risk of nontreatment 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 nontreatmentis associated with
`a high probability of significant morbidity or mortality to the maternal patient and the fetus.
`
`8.3 Nursing Mothers
`
`Adequate replacement doses of thyroid hormones are required to maintain normallactation. There are
`no reported cases of Levothyroxine Sodium for Injection used to treat myxedema coma in patients who
`are lactating. However, such patients should be treated with Levothyroxine Sodium for Injection as the
`risk of nontreatment is associated with 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 formof 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 geriatric 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 knowncardiacrisk factors is
`advised. Atrial fibrillation is a common side effect associated with levothyroxine treatmentin the
`elderly [see Dosage and Administration (2) and Warnings and Precautions(5)].
`
`10 OVERDOSAGE
`
`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 beenreported. 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 discontinued if signs or
`symptoms of overdosage occur. To obtain up-to-date information aboutthe 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 beinitiated as dictated 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 C;5HjgI4NNaOug, a molecular weight of
`
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`798.85 g/mol (anhydrous), and the following structural formula:
`
`|
`
`|
`
`HO
`
`O
`
`Ho
`
`HN
`CH.-C-—COO-Na*
`
`Levothyroxine Sodium for Injection is a sterile, preservative-free lyophilized powder consisting of the
`active ingredient, levothyroxine sodium, and the excipients dibasic sodium phosphate heptahydrate,
`USP; mannitol, USP; and sodium hydroxide, NF in single-use amber glass vials. Levothyroxine Sodium
`for Injection is available at three dosage strengths: 100 mcg per vial, 200 mcg pervial and 500 mcg per
`vial.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Thyroid hormones exert their physiologic actions through control of DNAtranscription and protein
`synthesis. Triiodothyronine (T3) and levothyroxine (T 4) 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 RNAand cytoplasmic proteins.
`
`The physiological actions of thyroid hormones are produced predominantly by T3, the majority of
`which (approximately 80%) is derived from Ty by deiodination in peripheral tissues.
`
`12.2 Pharmacodynamics
`
`Thyroid hormone synthesis and secretionis regulated by the hypothalamic pituitary-thyroid axis.
`Thyrotropin releasing hormone (TRH) released from the hypothalamus stimulates secretion of
`thyrotropin stimulating hormone (TSH) fromtheanterior 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 Ty levels exert a feedback effect on both TRH and TSHsecretion. When
`serum T3 and Ty, levels increase, TRH and TSH secretion decrease. When thyroid hormone levels
`decrease, TRH and TSH secretionincreases. 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,
`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 equivalent) and octreotide (greater than
`100 mcg per day).
`
`Thyroid hormones regulate multiple metabolic processes and play an essential role innormal growth
`and development, and normal maturation of the central nervous systemand bone. The metabolic actions
`of thyroid hormonesinclude 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
`
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`Abs orption — Levothyroxine Sodium for Injection is administered via the intravenous route. Following
`administration, the synthetic levothyroxine cannot be distinguished from the natural hormonethat is
`secreted endogenously.
`
`Dis tribution — 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. Thehigheraffinity of both TBG and TBPAfor Ty
`partially explains the higher serum levels, slower metabolic clearance, and longer half life of T4
`compared to T3. Protein bound thyroid hormones exist inreverse equilibrium with small amounts of
`free hormone. Only unbound hormoneis 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 Usein Specific Populations (8)].
`
`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 degradation for both Ty and T3, with Ty
`deiodination also occurring at a numberof additional sites, including the kidney and other tissues.
`Approximately 80% of the daily dose of T,4 is deiodinated to yield equal amounts of T3 and reverse T3
`(r T3). T3 andr 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 portionof 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 Parameters of Thyroid Hormonesin Euthyroid Patients
`
`Ratio in_Biologic Half-Life osa
`Borner ThyroglobulinPotency (Days) ea
`Ty
`10 to 20
`1
`6to8!
`99.96
`T3
`1
`4
`<2
`99.5
`
`T4: Levothyroxine
`
`T3: Liothyronine
`1 3 to 4 days inhyperthyroidism, 9 to 10 days in hypothyroidism.
`? Includes TBG, TBPA,and TBA.
`
`Drug Interactions
`
`A listing of drug interaction with Ty is provided in the following tables, although it may not be
`comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the
`discovery of previously unknown interactions. The prescriber should be awareof this fact and should
`consult appropriate reference sources (e.g., package inserts of newly 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
`Increase Serum
`TBG
`
`Drugs That May Decrease Serum TBG
`Concentration
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`Androgens / Anabolic Steroids
`Asparaginase
`§Glucocorticoids
`Slow-Release Nicotinic Acid
`
`Concentration
`Clofibrate
`Estrogen-
`containing oral
`contraceptives
`Estrogens (oral)
`Heroin /
`Methadone
`5-Fluorouracil
`Mitotane
`Tamoxifen
`
`Drugs That May Cause Protein-Binding Site
`
`Dis placement
`Potential impact: Administration of these agents with levothyroxine results in aninitial transient increase
`inFT4. Continued administration results ina decrease inserum Ty and normal FT4 and TSH
`concentrations and, therefore, patients are clinically euthyroid.
`Salicylates (> 2
`Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. Aninitial increase
`g/day)
`inserum FT, is followed by return of FT, to normal levels with sustained
`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 Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, andtotal-
`Hydantoins
`and free- T4 may be reduced by 20% to 40%, but mostpatients have normal serum TSH
`levels and are clinically euthyroid.
`
`Other drugs:
`Phenobarbital
`Rifampin
`
`Table 4: Drugs That May Decrease Conversionof T, to T3
`
`Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4
`to T3, leading to decreased T3 levels. However, serum Ty levels are usually normal but may
`occasionally be slightly increased.
`
`Drug or Drug
`
`tee
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`ELIecl
`
`Class
`Beta-adrenergic In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels
`antagonists
`change slightly, TSH levels remain normal, and patients are clinically euthyroid. It
`(e.g.
`should be noted that actions of particular beta-adrenergic antagonists may be impaired
`Propranolol > whenthe hypothyroidpatient is converted to the euthyroidstate.
`160 mg/day)
`Glucocorticoids Short-term administration of large doses of glucocorticoids may decrease serum T3
`(e.g.
`concentrations by 30% with minimal change inserum Ty levels. However, long-term
`Dexamethasone glucocorticoid therapy may result in slightly decreased T'3 and Ty levels due to
`> 4 mg/day)
`decreased TBG production (see above).
`
`Other drug:
`Amiodarone
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairmentof Fertility
`
`Animal studies have not been performed to 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.
`
`14 CLINICAL STUDIES
`
`Noclinical 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.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`Levothyroxine Sodium for Injection is available in three dosage strengths.
`
`Product NDC
`No.
`No.
`506107 63323-649-07
`506247 63323-647-10
`506248
`63323-648-10
`
`Reconstituted
`Concentration
`Strength
`20 mcg/mL
`100 mcg/vial
`200 mcg/vial 40 mcg/mL
`500 mcg/vial
`100 mcg/mL
`
`16.2 Storage and Handling
`
`Protect from light and store dry productat 20° to 25°C (68° to 77°F) [see USP Controlled Room
`Temperature]. Reconstituted drug product is preservative free. Discard any unused portion.
`
`This container closure is not made with natural rubber latex.
`
`Mylan Ex 1034, Page 10
`
`Mylan Ex 1034, Page 10
`
`

`

`aAPP
`Fresenius Kabi USA, LLC
`Lake Zurich, IL 60047
`
`451253C
`
`Revised: April 2013
`
`PACKAGE LABEL - PRINCIPAL DISPLAY- Levothyroxine 100 mcg Single Use Vial Label
`
`NDC 63323-649-07
`
`506107
`
`Levothyroxine Sodium for Injection
`
`100 mcg/vial
`
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion,
`
`Rx only
`
`NDC 63323-649-07 506107
`LEVOTHYROXINE
`SODIUM
`FOR INJECTION
`Teney
`ForIntravenous Use
`SingleUseVial
`Discard any unusedportion.
`a
`
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`a
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`ads
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`SS ESSHE BSheSase ge
`$isc Jig aatheies 23
`
`402595B
`
`LOT/EXP
`
`63323-649-074
`
`3
`
`PACKAGE LABEL - PRINCIPAL DISPLAY- Levothyroxine 100 mcg Single Use Vial Carton
`Panel
`
`NDC 63323-649-07
`
`506107
`
`Levothyroxine Sodium for Injection
`
`100 mcg/vial
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`Mylan Ex 1034, Page 11
`
`Mylan Ex 1034, Page 11
`
`

`

` mm
`
`NDC 63323-649-07 506107
`
`LEVOTHYROXINE
`SODIUM
`FOR INJECTION
`LITT I
`
`For Intravenous Use
`
`Single Use Vial
`Discard any unused
`portion.
`Rx only
`
`APP
`
`PACKAGELABEL - PRINCIPAL DISPLAY- Levothyroxine 500 mcg Single Use Vial Label
`
`NDC 63323-648-10
`
`506248
`
`Levothyroxine Sodium for Injection
`
`500 mcg/vial
`
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion,
`
`Rx only
`
`ForIntravenous Use
`Single Use Vial
`P
`a
`Discardany
`unused portion.
`ny
`Rx only
`
`402647A
`
`LOT/EXP
`
`EESSeesET
`NDC 63323-648-10
`506248
`3
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`
`363323-648-107
`
`Mylan Ex 1034, Page 12
`
`Mylan Ex 1034, Page 12
`
`

`

`PACKAGELABEL- PRINCIPAL DISPLAY- Levothyroxine 500 mcg Single Use Vial Carton
`Panel
`
`NDC 63323-648-10
`
`506248
`
`Levothyroxine Sodium for Injection
`
`500 mcg/vial
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`a ee
`NDC 63323-648-10
`506248
`
`LEVOTHYROXINE
`SODIUM
`FOR INJECTION
`
`For Intravenous Use
`
`Single UseVial
`Discard any unused
`portion.
`Rx only
`
`PACKAGELABEL- PRINCIPAL DISPLAY- Levothyroxine 200 mcg Single Use Vial Label
`NDC 63323-647-10
`
`506247
`
`Levothyroxine Sodium for Injection
`
`200 mcg/vial
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`Mylan Ex 1034, Page 13
`
`Mylan Ex 1034, Page 13
`
`

`

`NDC 63323-647-10
`
`506247
`
`LEVOTHYROXINE
`SODIUM
`FOR INJECTION
`
`200 meg/vial
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`
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`PACKAGE LABEL - PRINCIPAL DISPLAY- Levothyroxine 200 mcg Single Use Vial Carton
`Label
`
`NDC 63323-647-10
`
`506247
`
`Levothyroxine Sodium for Injection
`
`200 mcg/vial
`
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`Mylan Ex 1034, Page 14
`
`Mylan Ex 1034, Page 14
`
`

`

`aaa = ee
`
`NDC 63323-647-10
`506247
`LEVOTHYROXINE
`SODIUM
`FOR INJECTION
`ETT
`
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused
`portion.
`
`Rx only
`
`aAPP
`
`
`LEVOTHYROXINE SODIUM
`
`levothyroxine sodium anhydrousinjection, powder, lyophilized, for solution
`
`Product Information
`
`Product T ype
`
`HUMAN PRESCRIPTION DRUG
`
`Item Code (Source)
`
`NDC:6 3323-647
`
`Route of Administration
`
`INTRAVENOUS
`
`Active Ingredient/Active Moiety
`Ingredient Name
`LEVOTHYROXINE SO DIUM ANHYDROUS(UNII: 054136 CPMN)
`(LEVOTHYROXINE - UNIQ51B043MG4)
`
`Basis of Strength
`LEVOTHYROXINE SODIUM
`ANHYDROUS
`
`Strength
`200 ug
`inS mL
`
`Inactive Ingredients
`
`Ingredient Name
`
`Strength
`
`MANNITOL (UNI: 30 WL53L36 A)
`SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE(UNII: 70 WT22SF4B)
`
`SODIUM HYDRO XIDE (UNII: 55X04QC321)
`
`Mylan Ex 1034, Page 15
`
`Mylan Ex 1034, Page 15
`
`

`

`Packaging
`#
`Item Code
`1 NDC:63323-647-10
`
`1
`
`Package Description
`lin 1 CARTON
`
`5 mL in 1 VIAL, SINGLE-USE
`
`Marketing Start Date
`
`Marketing End Date
`
`Marketing Information
`Marketing Category
`Application Number or Monograph Citation Marketing St