LEVOTHYROXINE SDDIUM- 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 TREATMENT OF OBESITY OR FOR WEIGHT LOSS
`
`Thyroid ho rmones,including Levothyroxine Sodium for Injection, should not be used lorthe treatment
`of obesity or for weight loss. (5.3)
`Larger doses may produce serious or even life threatening rnanifestatio 115 of toxicity. (6)
`
`---------------------------------------- -- INDICATIONS
`
`Levothyroxine Sodium is an L-[hyroxine product. Levothyroxine (T4) 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.
`------------------------------------- --DOSAGEANDADMINISTRATION ---------------------------------------
`
`0 An initial intravenous loading dose ofLevothyroxine 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)
`I Reconstitute the lyophiiized Levothyroxine Sodium for Injection by aseptically adding 5 mLofD.9% Sodium Chloride
`Injection, US P. Shake vial to ensure complete mixing. Reconstituted drug product is preservative free. Use
`immediately after reconstitution. Discard any unused portion. [2.3_)
`0 Do not add to other IV fluids. (2.3)
`
`------------------------------------ -- DOSAGEFORMS AND STRENGTHS
`
`Lyophilized powder for injection in single use vials; 100 mcg, 200 mcg and 500 mcg. (3)
`------------------------------------------ --CONTRAINDICATIONS
`None. (4)
`-------------------------------------- -‘WARNINGS ANDPRECAUTIONS —---------------------------------------
`
`Excessive bolus doses ofLevothyroxine 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 ofthe recommended range. (5.1)
`Close observation ofthe patient following the administration of Levothyroirine 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 predispose to signs and symptoms compatible with hyperthyroidism. (6)
`(5)
`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.govfmedwatch. (6)
`------------------------------------------ -- DRUGINTERACTIONS---------------------------------------------
`
`Many drugs af-Fect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism,
`protein binding, and target tissue response)and may alter the therapeutic response to Levothyroxine Sodium for Injection.
`(7,123)
`------------------------------------- -- USE IN SPECIFIC POPULATIONS ---------------------------------------
`
`I Elderly and those with underlying cardiovascular disease should receive doses at the lower end ofthe recommended
`range.(8.5)
`
`Revised: 12r2o 13
`
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`
`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosage
`2.2 Dosing in the 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 Airticoagulants
`7.3 Digitalis Glycosides
`7.4 Antidepressant Therapy
`7.5 Ketamine
`
`7.6 Syrnpathotnirnetics
`7.7 Drug-Laboratory Test Interactions
`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 Mechanismof Action
`
`12.2 Pharmacodynamics
`12.3 Pharrnacokinetics
`13 NONCLINICAL TOXIC OLOGY
`
`13.1 Carcinogenesis, Mutagenesis,IIIpairm31rt 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
`
`Mylan Ex 1034, Page 2
`
`

`
`WARNING: NOT FOR TREATMENT 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)
`
`1 INDICATIONS AND USAGE
`
`Levothyroxine Sodium for Injection is indicated for the treatmentof 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
`
`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. 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 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
`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 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,
`Inyocardial 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 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 and 100 mcg per mL
`for the 100 mcg, 200 mcg and 500 mcg vials, respectively. Reconstituted drug product is 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
`
`Mylan Ex 1034, Page 3
`
`

`
`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 arrhythrnias, tachycardia, myocardial ischemia and
`infarction, or worsening of congestive heart failure 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 occur in
`association with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and
`insulittldependent 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 Treatment of 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 weight loss. In euthyroid
`patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.
`Larger doses may produce serious or evenlife 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:
`exophthalrnic 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 pharmacoltinetics 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 varied
`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 inincreased antidiabetic agent or
`insulin requirements. 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 in the dose
`of anticoagulant Inay 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 when a hypothyroid patient becomes euthyroid, necessitating an
`increase in the dose of digitalis glycosides.
`
`7.4 Anlidepres s ant T he rapy
`
`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 syrnpathomimetics or thyroid hormone. Thyroid hormones
`may increase the risk of coronary insufficiency when sympathomimetic agents are administered to
`patients with coronary artery disease.
`
`7.7 Drug-Labo ratory 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 andfor 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
`
`Mylan Ex 1034, Page 5
`
`

`
`Pregnancy Category A — There are no reported cases of Levothyroxine Sodium for Injection used to
`treat myxederna coma in patients who were pregnant or lactating. Studies in pregnant women treated with
`oral levothyroxine to maintaina euthyroid state have not shown an increased risk of fetal abnormalities.
`Therefore, pregnant patients who develop myxedema should be treated with Levothyro;-tine 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 myxederna have notbeen reported in the literature. However, 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 maternal patient and the fetus.
`
`8.3 Nursing Mothers
`
`Adequate replacement doses of thyroid hormones are required to maintain normal lactation. The re 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 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 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 known cardiac risk factors is
`advised. Atrial fibrillation is a common side effect associated with levothyroxine treatment in the
`elderly [see Dosage and Administration (2) and Warnings and Precautions (5)}.
`
`10 OVERDOSAGE
`
`In general, the signs and symptoms of overdosage with levodiyroxine 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 Overdos age
`
`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 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 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-15H10I4NNaO4, a molecular weight of
`
`Mylan Ex 1034, Page 6
`
`

`
`798.85 g/rnol (anhydrous), and the following structural formula:
`
`I
`
`I
`
`H2
`
`cH2—E:—coo-r~xa+
`
`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 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 and 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 Pharlnacodynamics
`
`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 mechanisnrs and those
`examples are diazepam, ethioamide, lovastatin, metoclopramide, 6—mercaptopurine, nitroprusside,
`perphenazine, and thiazide diuretics. Some drugs may cause atransierrt decrease ir1TSH 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 in 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
`
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`
`

`
`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 prealburnin (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 serumlevels, slower metabolic 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 Use in 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 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: Pharrnacokinetic Parameters of Thyroid Hormones in Euthyroid Patients
`
`Ratio in
`Biologic Half-Life
`Hormone Thyroglo bulin Potency (Days)
`
`10 to 20
`1
`
`1
`4
`
`6 to 81
`2 2
`
`Protein
`
`Binding
`(%)2
`99.96
`99.5
`
`: Levothyroxine
`
`: Liothyro nine
`
`1 3 to 4 days in hyperthyroidism, 9 to 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 thyroidal 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 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
`
`Mylan Ex 1034, Page 8
`
`

`
`Androgens I Anabolic Steroids
`Asparaginase
`Glucocorticoids
`Slow-Release Nicotinic Acid
`
`Concentration
`
`Clofibrate
`Estrogen—
`containing oral
`contraceptives
`Estrogens (oral)
`Heroini’
`Methadone
`5-Fluorouracil
`Mitotane
`Tamoxifen
`
`Drugs That May Cause Protein-Binding Site
`
`Displacement
`Potential impact: Administration of these agents with levothyroxine results in an initial transient increase
`in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH
`concentrations and, therefore, patients are clinically euthyroid.
`
`Salicylates (> 2
`g/day)
`
`Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase
`in serum FT4 is followed by return of FT4 to normal levels with sustained
`therapeutic serum salicylate concentrations, although total-T4 levels may decrease
`by as much as 30%.
`
`Other drugs:
`Furosemide [> 80
`F113 W)
`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 carbaniazepine reduce serum protein binding of levoihyroxine, and total-
`Hydarrtoins
`and free— T4 may be reduced by 20% to 40%, but most patients have normal serumTSH
`levels and are clinically euthyroid.
`
`Other drugs:
`Phenobarbital
`
`Rifanpin
`
`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 slightly increased.
`
`Drug or Drug
`
`Mylan Ex 1034, Page 9
`
`

`
`Clas s
`
`l'_‘aI.lC|.'l
`
`Beta—adrenergic In patients treated with large doses of propranolol (> 160 mgfday), 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 > when the hypothyroid patient is converted to the euthyroid state.
`160 mg/day)
`
`Glucocorticoids Short—term administration of large doses of glucocorticoids may decrease serum T3
`(e.g.
`concentrations by 30% with minimal change in serum T4 levels. However, long—term
`Dexamethasone glucocorticoid therapy Inay result in slightly decreased T3 and T4 levels due to
`3 4 mg/day)
`decreased TBG production (see above).
`
`Other drug:
`Amiodarone
`
`13 NONCLINICAL T OXIC OLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of 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
`
`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.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`Levothyroxine Sodium for Injection is available in three dosage strengths.
`
`Product NDC
`
`Recons tituted
`
`_No.
`No.
`506107 63323-649-07
`506247
`_6 3323-64 7-10
`506248
`63323-648-10
`
`_Concentration
`Strength
`20 mcg/mL
`100 mcg/vial
`200 mcg/vial 40 mcgfmL
`500 mcg/vial
`100 mcg/mL
`
`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
`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
`
`

`
`a=AF’P
`Fresaniun Kabi USA. LLC
`lake Zurich. IL SIM?
`
`451253C
`
`Revised: April 2013
`
`PACKAGE LABEL — PRINCIPAL DISPLAY — Levothyroxine 100 mcg Single Use Vial Label
`
`NDC 63323-649-07
`
`506107
`
`Levothyruxine Sodium for Injection
`
`100 mcgfvial
`
`For Innavenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`NDC 63323-5494}? 50610?
`
`LEVOTHYHUXINE
`SODIUM
`F03 INJECTION
`
`10!] mcgfvial
`Fortnrauelruis Use
`
`Single use Val
`Discml any unused portion.
`Rx onty
`
`
`
`5‘|l|'II.Lynfllllml
`
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`
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`
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`
`
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`
`
`
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`
`npnm,USP.91dmidmEmI.rBsntllumI1aqtttzllyaddru5rnLIi0.9%Sa:|u1IEiitrizls
`
`402595B
`
`
`
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`
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`
`Discardanyunnml{mmPreseriusKablUSA.LLcLakezurth,ILao:-4:-'
`
`363323-349074
`
`PACKAGE LABEL — PRINCIPAL DISPLAY — Levuthyruxine 100 mcg Single Use Vial Carton
`Panel
`
`NDC 63323—649~07
`
`506107
`
`Levothyroxine Sodium for Injection
`
`100 mcgfvial
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion
`
`Rx only
`
`Mylan Ex 1034, Page 11
`
`

`
`I I —
`
`NDC -E3323-649-07 506107
`
`LEVOTHYHOXINE
`SODIUM
`FOR INJECTION
`
`II
`
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused
`portion.
`
`Rx only
`
`4—\PP
`
`PACKAGE LABEL — 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
`
`HDC 53323-6411 -10
`
`506248
`
`LEVUTHYFIOXINE
`SODIUM
`FUR INJEC HON
`
`For intravenous Use
`
`Single Ilse Vial
`Discad any unused portim.
`Fix only
`
`
`
`Stanla,LynplnlmaPIIIIIIIHIFIB!
`
`
`
`
`
`Earl‘!II3contains:Lavflhjrmine5odlurn5111mg;InaeflvaIngranhnts:memrlnnIahnl.UsualDmagaSeeInsert.
`
`
`
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`
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`
`
`
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`
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`
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`
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`
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`
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`
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`
`402547A
`
`363323-648407
`
`
`
`
`
`FrounIu:IublUSA.LLCLnzuacn.ILcow
`
`
`
`
`
`Iullon.DIsca‘I:|anyunusedportlm.
`
`Mylan Ex 1034, Page 12
`
`

`
`PACKAGE LABEL - PRINCIPAL DISPLAY - Levothyroxine 500 mcg Single Use Vial Carton
`Panel
`
`NDC 63323-648-10
`
`506248
`
`Levothyroxine Sodium for Injection
`
`500 meg/vial
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`— — I I
`NDC 63323-648-10
`506243
`
`LEUOTHYHOXINE
`SUDI UM
`FOR INJECTION
`
`For Intravenous Use
`
`Single Use ‘dial
`
`Discard any unused
`portion.
`
`Flx only
`
`PACKAGE LABEL - PRINCIPAL DISPLAY - Levothyroxine 200 mcg Single Use Vial Label
`NDC 63323-647-10
`
`506247
`
`Levothyroxine Sodium for Injection
`
`200 mcgfvial
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`Mylan Ex 1034, Page 13
`
`

`
`NBC 63323-64?-10
`
`506247
`
`LEVUTHYROXINE
`SODIUM
`
`FOR INJECTION
`
`200 mcglvial
`Fotinravertuususe
`
`Singleusevial
`
`Di9caIdaI1yunLI9edpurIim.
`
`Rxnnly
`
`SE3.E...It
`
`
`
`§___;__g._exam
`
`_5_§:_85.5._s_E$..23.:m__.E-2.5age.3.5_uae_.a_525E~___,_3..
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`
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`
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`
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`
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`
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`
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`
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`
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`
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`
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`
`PACKAGE LABEL - PRINCIPAL DISPLAY - Levnthyroxine 200 mcg Single Use Vial Carton
`Label
`
`NDC 63323—647—1(}
`
`Levothyroxine Sodium for Injection
`
`200 meg/vial
`
`For Intravenous Use
`
`Single Use Vial
`
`Discard any unused portion.
`
`Rx only
`
`Mylan Ex 1034, Page 14
`
`

`
`— - I
`
`NDC 63323-347-10
`
`506247
`
`LEVDTHYROXINE
`SODIUM
`FOR INJECTION
`
`II
`
`For Intravenous Use
`
`Singte Use Vial
`
`Discard any unused
`portion.
`
`Fix only
`
`LEVOTHYROXINE SODIUM
`
`levorhyroxine sodium anhydrous injection, powder, lyophilized, for solution
`
`Product Information
`
`Product Type
`
`HUMAN PRESCRIPTION DRUG
`
`Item Code (S nurce)
`
`NDC1-73323-6 47
`
`Route of Ad ministratio n
`
`INTRAVENOUS
`
`Active Ingredient/Active Moiety
`
`Ingredient Name
`LEVO Tl-IYROXINE SD DIUM ANHYDROUS (UNIIZ 054I36CPMN)
`(LEVOTHYROXINE - UN]1:Q5]BO43MG4)
`
`Basis of Strength
`LE.\«’OTH‘1"ROXINE SODIUM
`ANHYDROUS
`
`Strength
`200 ug
`in 5 mL
`
`Inactive Ingredients
`
`Ingredient Name
`
`Strength
`
`MANNITOL [UNI]: 3OWL53L36 A)
`SODIUM PHD SPHATE, DIBASIC, HEPTAHYDRATE [UNI]: 70WT22SF4B)
`
`SODIUM HYDRO XIDE (UNII: SSXU4-QC32l)
`
`Mylan Ex 1034, Page