Levothyroxine Sodium

DESCRIPTION

LevothyroxineSodium 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 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 two dosage strengths: 100 mcg per vial and 200 mcg per vial.

INDICATIONS

Levothyroxine Sodium for Injection is indicated for the treatment ofmyxedema 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.

DOSAGE AND ADMINISTRATION

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 and is clinically stable. For chronic treatment ofhypothyroidism, an oral dosage form of levothyroxine should be used to maintain aeuthyroidstate. 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 andthyroid hormonelevels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly.

Dosing In The Elderly And In Patients With Cardiovascular Disease

Intravenous levothyroxine may be associated with cardiac toxicity–including arrhythmias,tachycardia, myocardialischemiaandinfarction, or worsening ofcongestive heart failureand death–in the elderly and in those with underlyingcardiovascular disease. Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations.

Reconstitution Directions

重建的冻干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 and 40 mcg per mL for the 100 mcg and 200 mcg vials, respectively. Reconstituted drug product is preservative free and is stable for 4 hours. Discard any unused portion. DO NOTADDLEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS.Parenteraldrug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Dosage Forms And Strengths

Levothyroxine Sodium for Injection is supplied as a lyophilized powder at two strengths in single use amber-colored vials: 100 mcg and 200 mcg.

Levothyroxine Sodium for Injection is available in two dosage strengths.

Product No.	NDC No.	Strength	Reconstituted Concentration
NP506107	63323-649-16	100 mcg/vial	20 mcg/mL
NP506247	63323-647-11	200 mcg/vial	40 mcg/mL

Storage And Handling

Protect from light and store dry product at 20° to 25°C (68° to 77°F) [seeUSP Controlled Room Temperature]. Reconstituted drug product is preservative free. Discard any unused portion.

This container closure is not made with natural rubber latex.

Manufactured by: FreseniusKabi USA, LLC, Lake Zurich, IL 60047. Revised: Aug 2014

SIDE EFFECTS

Excessive doses of levothyroxine canpredisposeto signs and symptoms compatible with hyperthyroidism. The signs and symptoms of thyrotoxicosis include, but are not limited to: exophthalmicgoiter, weight loss, increased appetite,palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increasedpulseand blood pressure, cardiac arrhythmias,angina pectoris, tremors, insomnia, heat intolerance, fever, and menstrual irregularities.

DRUG INTERACTIONS

Many drugs affectthyroidhormone pharmacokinetics andmetabolism(e.g., synthesis, secretion,catabolism、蛋白结合和目标)和组织反应may alter the therapeutic response to Levothyroxine Sodium for Injection. In addition,thyroid hormonesand thyroid status have varied effects on the pharmacokinetics and actions of other drugs (seePharmacokinetics).

Antidiabetic Therapy

Addition of levothyroxine to antidiabetic orinsulintherapy may result in increasedantidiabetic agent或胰岛素需求。仔细监控diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.

Oral Anticoagulants

Levothyroxine increases the response to oralanticoagulant治疗。因此,减少剂量的抗coagulant may be warranted with correction of the hypothyroid state or when the Levothyroxine Sodium for Injection dose is increased.Prothrombin timeshould be closely monitored to permit appropriate and timely dosage adjustments.

洋地黄苷

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.

Antidepressant Therapy

Concurrent use of tricyclic (e.g.,amitriptyline) or tetracyclic (e.g., maprotiline)antidepressantsand 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.

Ketamine

Concurrent use may produce markedhypertensionand tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.

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 withcoronary artery disease.

Drug-Laboratory Test Interactions

Changes in thyroxine binding globulin (TBG) concentration must be considered when interpreting levothyroxine andtriiodothyroninevalues, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free levothyroxine index. Pregnancy,infectious hepatitis,estrogens,estrogencontaining oral contraceptives, and acute intermittentporphyriaincrease TBG concentrations. Decreases in TBG concentrations are observed innephrosis, severe hypoproteinemia, severeliver disease,acromegaly, and afterandrogenor皮质类固醇治疗。Familialhyper or hypo thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9,000.

警告

Included as part of thePRECAUTIONSsection.

PRECAUTIONS

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 congestiveheart failureand 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.

Need For Concomitant Glucocorticoids And Monitoring For Other Diseases In Patients With Endocrine Disorders

Occasionally, chronicautoimmune thyroiditis, which can lead to myxedema coma, may occur in association with otherautoimmunedisorders such as adrenal insufficiency,pernicious anemia, and insulin-dependentdiabetes 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 thyroidhormone therapyis 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 undiagnoseddiabetes insipidus.

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 ofobesityor for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for theiranorecticeffects [seeADVERSE REACTIONSandOVERDOSAGE].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Animal studies have not been performed to evaluate thecarcinogenicpotential, mutagenic potential or effects on fertility of Levothyroxine Sodium for Injection.

Use In Specific Populations

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 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.

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.

Nursing Mothers

Adequate replacement doses of thyroid hormones are required to maintain normal lactation. There are no reported cases of Levothyroxine Sodium for Injection used to treat myxedema coma in patients 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.

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.

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 increasedprevalenceofcardiovasculardisease in the elderly, cautious use of Levothyroxine Sodium for Injection in the elderly and in patients with known cardiac risk factors is advised.Atrial fibrillationis a common side effect associated with levothyroxine treatment in the elderly [seeDOSAGE AND ADMINISTRATIONand警告AND PRECAUTIONS].

OVERDOSE

In general, the signs and symptoms of overdosage with levothyroxine are those of hyperthyroidism [see警告ANDPRECAUTIONSandADVERSE REACTIONS]. In addition, confusion and disorientation may occur. Cerebralembolism,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 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 drugkineticsin the patient. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's medical status.

CONTRAINDICATIONS

None.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Thyroid hormones exert theirphysiologicactions through control of DNAtranscriptionand protein synthesis. Triiodothyronine (T₃) and levothyroxine (T₄) diffuse into the cellnucleusand bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis ofmessenger RNAand cytoplasmic proteins.

The physiological actions of thyroid hormones are produced predominantly by T , the majority of which (approximately 80%) is derived from T by deiodination in peripheral tissues.

Pharmacodynamics

Thyroid hormone synthesis and secretion is regulated by the hypothalamicpituitary-thyroidaxis.Thyrotropinreleasing hormone (TRH) released from thehypothalamusstimulates secretion of thyrotropin stimulating hormone (TSH) from theanterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, T₄and T₃, by thethyroid gland. Circulating serum T₃and T₄levels exert a feedback effect on both TRH and TSH secretion. When serum T₃and T₄levels 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 [seeDosage].

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) aredopamine(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 anessentialrole in normal growth and development, and normal maturation of thecentral nervous systemand bone. The metabolic actions of thyroid hormones include augmentation of cellularrespirationand thermogenesis, as well as metabolism of proteins,carbohydratesandlipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development.

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 bindingprealbumin(TBPA), and专辑in(TBA), whose capacities and affinities vary for each hormone. The higheraffinityof both TBG and TBPA for T₄partially explains the higher serum levels, slower metabolic clearance, and longer half life of T₄compared 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警告ANDPRECAUTIONSandDRUG INTERACTIONS]. Thyroid hormones do not readily cross the placental barrier [see警告ANDPRECAUTIONSandUse in Specific Populations].

Metabolism

T₄is slowly eliminated. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately eighty percent of circulating T₃is derived from peripheral T₄by monodeiodination. The liver is the major site of degradation for both T₄and T₃, with T₄deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T₄is deiodinated to yield equal amounts of T₃and reverse T₄(r T₃). T₃and r T₃are further deiodinated todiiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into thebileand gut where they undergo enterohepatic recirculation.

Elimination

Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches thecolonunchanged, where it is hydrolyzed and eliminated in feces as the free hormones. Urinary excretion of T₄decreases with age.

Table 1: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone	Ratio in Thyroglobulin	Biologic Potency	Half-Life (Days)	Protein Binding (%)2
T4	10 to 20	1	6 to 81	99.96
T3	1	4	< 2	99.5
T4: Levothyroxine T3: Liothyronine 13 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism. 2Includes TBG, TBPA, and TBA.

Drug Interactions

A listing of drug interaction with T₄is 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 T₄and T₃Serum Transport Without Affecting free T₄Concentration (Euthyroidism)

Drugs That May Increase Serum TBG Concentration	Drugs That May Decrease Serum TBG Concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
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 T4and normal FT4and TSH concentrations and, therefore, patients are clinically euthyroid.
Salicylates ( > 2 g/day)	Salicylates inhibit binding of T4and T3to TBG and transthyretin. An initial increase in serum FT4is followed by return of FT4to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4levels 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 reduce serum protein binding of levothyroxine, and total- and free- T4may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Other drugs: Phenobarbital Rifampin

Table 4: Drugs That May Decrease Conversion of T₄to T₃
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T₄to T₃, leading to decreased T₃levels. However, serum T₄levels are usually normal but may occasionally be slightly increased.

Drug or Drug Class	Effect
Beta-adrenergic antagonists (e.g.Propranolol > 160 mg/day)	In patients treated with large doses of propranolol ( > 160 mg/day), T3and T4levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state.
Glucocorticoids (e.g. Dexamethasone ≥ 4 mg/day)	Short-term administration of large doses of glucocorticoids may decrease serum T3concentrations by 30% with minimal change in serum T4levels. However, long-term glucocorticoid therapy may result in slightly decreased T3and T4levels due to decreased TBG production (see above).
Other drug: Amiodarone

Animal Toxicology And Pharmacology

No animaltoxicologystudies have been conducted with Levothyroxine Sodium for Injection.

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.

PATIENT INFORMATION

No information provided. Please refer to the警告ANDPRECAUTIONSsections.