(-)-Thyroxine

776.870

776.87

200-101-1

Q51BO43MG4

757434

DTXSID8023214

C62080

Crystals|Needles

H03AA01|H - Systemic hormonal preparations, excl. sex hormones and insulins

2922509090

92.78000

2.4

Solid

2.6±0.1 g/cm3

235-236 °C (decomp)

576.3±50.0 °C at 760 mmHg

302.3±30.1 °C

1.795

insoluble

Keep container tightly closed in a dry and well-ventilated place.

2.05X10-16 mm Hg at 25 deg C (est)

TDLo oral in child: 328ug/kg

Specific optical rotation: -4.4 deg at 20 °C/D (3% in 0.13N sodium hydroxide in 70% ethanol)

Henry's Law constant = 7.91X10-19 atm-cu m/mol at 25 °C (est)

pKa1 = 0.27 (carboxylic); pKa2 = 7.43 (phenol); pKa3 = 9.43 (amine) (est)

216.2 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]|194.19 Ų [M+Na-2H]- [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]|208.3 Ų [M-2H+Na]-

log Kow = 0.16-2.11|Occurs as the hydrate. Triclinic crystals or cream-colored powder; odorless, teasteless, somewhat hygroscopic. Density: 2.381 at 20 °C/4 °C. Specific optical rotation: -4.4 deg at 20 °C/D (C = 3 in 70% ethanol). Solubility in water (25 °C): about 15 mg/100 mL. Soluble in mineral acids and in solutions of alkalies it dissolves and hot solutions of alkyl carbonates. Slightly soluble in alcohol. Insoluble in acetone, chloroform, ether. pH of saturated water solution: 8.35 to 9.35 /Thyroxine sodium salt/|Needle-like crystals. Decomposes 231-233 °C. Insoluble in water, alcohol and in the other usual organic solvents; in the presence of mineral acids or alkalies it dissolves in alcohol; soluble in solutions of the alkali hydroxides and in hot solutions of the alkali carbonates /DL-Thyroxine/|Crystals, decoposes at 237 °C. Specific optical rotaion: +2.97 deg at 21 °C/546 mm Hg (0.74 g in 6 g og 0.5N sodium hydroxide and 14 g alcohol) /D-Thyroxine/

NONH for all modes of transport

3

R20/21/22

S22-S24/25

YP2833500

Xn:Harmful

Extemporaneously prepared liquid dosage forms are needed to administer required medications in infants and young children. The goal of this study was to evaluate the stability of levothyroxine in extemporaneously prepared suspensions stored in plastic prescription bottles under refrigeration and room temperature. Levothyroxine (25 ug/mL) /was/ prepared in two groups of suspensions. /The/ suspensions were stored in plastic prescription bottles under refrigeration and at room temperature. Levot

P210-P260-P280-P301 + P310 + P330-P302 + P352 + P312-P370 + P378

H225-H301 + H311 + H331-H370

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents, Strong bases

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including levothyroxine sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Levothyroxine sodium/

|Danger|H361 (94.23%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P260, P264, P270, P281, P308+P313, P314, P405, and P501|Aggregated GHS information provided by 52 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H302 (61.9%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P312, P308+P313, P314, P330, P405, and P501|Aggregated GHS information provided by 22 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Warning|H361: Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas; Environmental precautions: Do not let product enter drains; Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.|Appropriate engineering controls: General industrial hygiene practice.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

LD50=20 mg/kg (orally in rat). Hypermetabolic state indistinguishable from thyrotoxicosis of endogenous origin. Symptoms of thyrotoxicosis include weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, tremors, insomnia, heat intolerance, fever, and menstrual irregularities.|IDENTIFICATION AND USE: Levothyroxine occurs as crystals or needles. As a drug, levothyroxine sodium is used as replacement or supplemental therapy in congenital or acquired hypothyroidism. It is also used in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. The injection form of levothyroxine sodium is indicated for the treatment of myxedema coma. Levothyroxine has also been used in veterinary medicine. HUMAN EXPOSURE AND TOXICITY: The signs and symptoms of levothyroxine overdosage are those of hyperthyroidism. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Studies indicate that careful attention is necessary when initiating the administration of levothyroxine sodium to very-low-birth-weight infants. Ingestion of levothyroxine in children typically follows a benign course, but overdose can result in significant complications, including seizures and arrhythmias, both of which should be monitored for. In one genotoxicity study, the ability of thyroxine to induce sister chromatid exchange and micronuclei was tested in cultured human lymphocytes. Thyroxine exhibited weak clastogenic effects only at high concentrations. ANIMAL STUDIES: A single acute overdose in small animals is less likely to cause severe thyrotoxicosis than chronic overdosage. Vomiting, diarrhea, transition from hyperactivity to lethargy, hypertension, tachycardia, tachypnea, dyspnea, and abnormal pupillary light reflexes may be noted in dogs and cats. In dogs, clinical signs may appear within 1-9 hours after ingestion. Four pregnant New Zealand white rabbits received intramuscular levothyroxine at 250 ug/kg on days 25 and 26 of gestation. Maternal and fetal plasma-free levothyroxine concentration was higher than in controls, with the highest concentration noted at 14 days of neonatal period. Treatment resulted in fetal hyperglycemia and depletion of fetal liver glycogen content. Animal studies have not been performed to evaluate levothyroxine carcinogenic potential, mutagenic potential or effects on fertility.

There is little information on serum aminotransferase levels during thyroxine therapy, but it is a very commonly prescribed medication and, at conventional doses, has not been linked to serum enzyme elevations. High doses of levothyroxine and other thyroid preparations, however, can cause serum enzyme elevations, typically in a hepatocellular or mixed pattern. Indeed, spontaneous hyperthyroidism can be accompanied by serum enzyme elevations and even jaundice. Minor serum enzyme elevations may also accompany hypothyroidism or Hashimoto disease. The liver test abnormalities accompanying hyper- or hypo-thyroidism generally resolve promptly with establishment of the euthyroid state.

Antacids (e.g., aluminum hydroxide, magnesium hydroxide, calcium carbonate), simethicone, and sucralfate bind thyroid agents in the GI tract and delay or prevent their absorption. Calcium carbonate may form an insoluble chelate with levothyroxine, resulting in decreased levothyroxine absorption and increased serum thyrotropin concentrations; in vitro studies indicate that levothyroxine binds to calcium carbonate at acidic pH levels. To minimize or prevent this interaction, some clinicians recommend that these agents be administered approximately 4 hours apart when the drugs must be used concurrently with thyroid agents.|Serum concentrations of digitalis glycosides may be decreased in patients with hyperthyroidism or in patients with hypothyroidism in whom a euthyroid state has been achieved. Thus, therapeutic effects of digitalis glycosides may be reduced in these patients.|Drugs that induce hepatic microsomal enzymes (e.g., carbamazepine, phenytoin, phenobarbital, rifampin) may accelerate metabolism of thyroid agents, resulting in increased thyroid agent dosage requirements. Phenytoin and carbamazepine also reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20-40%, but most patients have normal serum concentrations of thyrotropin (thyroid-stimulating hormone, TSH) and are clinically euthyroid. /Thyroid agents/|Bile acid sequestrants (e.g., cholestyramine resin, colestipol) bind thyroid agents in the GI tract and substantially impair their absorption. In vitro studies indicate that the binding is not readily reversible. To minimize or prevent this interaction, these agents should be administered at least 4 hours apart when the drugs must be used concurrently.|For more Interactions (Complete) data for LEVOTHYROXINE (14 total), please visit the HSDB record page.

In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis. If the serum TSH level is not suppressed, Synthroid should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.|Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids.|Exercise caution when administering levothyroxine to patients with nontoxic diffuse goiter or nodular thyroid disease in order to prevent precipitation of thyrotoxicosis. If the serum TSH is already suppressed, levothyroxine sodium should not be administered.|Exercise caution when administering levothyroxine to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease.

Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA) and albumin (TBA). The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, 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 where only unbound hormone is metabolically active.

Thyroxine is an essential thyroid hormone for normal development and physiology and is regulated by the pituitary gland in mammals(1-3).

Levothyroxine's production and administration as a medication to treat hypothyroidism and goiter in humans and animals(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6600(SRC), determined from a structure estimation method(2), indicates that levothyroxine is expected to be immobile in soil(SRC). Estimated pKa values of 7.43 and 9.43(3), indicating that this compound will exist as a zwitterion in the environment. Volatilization from moist soil is not expected because the compound exists as an ion and ions do not volatilize. Levothyroxine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil ere not available(SRC, 2016).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6600(SRC), determined from a structure estimation method(2), indicates that levothyroxine is expected to adsorb to suspended solids and sediment(SRC). Estimated pKa values of 7.43 and 9.43(3) indicate levothyroxine will exist as a zwitterion at pH values of 5 to 9 and, therefore, volatilization from water surfaces and bioconcetration are not expected to be an important fate processes. Biodegradation data in water were not available(SRC, 2016).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), levothyroxine, which has an estimated vapor pressure of 2.1X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase levothyroxine may be removed from the air by wet and dry deposition(SRC). Levothyroxine contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Levothyroxine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Levothyroxine contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Estimated pKa values of 7.43 and 9.43(1) indicate that levothyroxine will exist in the zwitterion form in the environment and, therefore, bioconcentration is not expected to be an important environmental fate process(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of levothyroxine can be estimated to be 6600(SRC). According to a classification scheme(2), this estimated Koc value suggests that levothyroxine is expected to be immobile in soil. Estimated pKa values of 7.43 and 9.43(3) indicate that this compound will exist almost entirely in the zwitterion form in the environment(3).

Estimated pKa values of 7.43 and 9.43(1) indicate levothyroxine will exist as a zwitterion at pH values of 5 to 9 and, therefore, volatilization from water surfaces and bioconcetration are not expected to be an important fate processes. Levothyroxine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-16 mm Hg(SRC), determined from a fragment constant method(2).

While data specific to levothyroxine were not located(SRC, 2016), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Levothyroxine (T4) is excreted into breast milk in low concentrations. ...

NIOSH (NOES Survey 1981-1983) has statistically estimated that 10,666 workers (7,298 of these are female) were potentially exposed to levothyroxine in the US(1). Occupational exposure to levothyroxine may occur through inhalation and dermal contact with this compound at workplaces where levothyroxine is produced or used. The general public is not likely to be exposed to levothyroxine unless by direct medical treatment(SRC).

Levothyroxine is indicated as replacement therapy in primary (thyroidal), secondary (pituitary) and tertiary (hypothalamic) congenital or acquired hypothyroidism. It is also indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Thyroid hormones used therapeutically include crude thyroid extracts as well as synthetic forms of L-thyroxine (levothyroxine, T4) and L-triiodothyronine (liothyronine, T3). Thyroid hormone plays an essential role in growth and development and regulates multiple metabolic processes that are responsible for functional homeostasis. When given in high doses, thyroid hormone preparations can cause mild serum enzyme elevations. In addition, standard doses of levothyroxine have been linked to rare instances of mild, immunoallergic liver injury.

Thyroid Agents

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Levothyroxine is included in the database.|Levothyroxine sodium is used ... as replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter. /Included in US product label/|Levothyroxine sodium is used ... in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. /Included in US product label/|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. /Included in US product label/|For more Therapeutic Uses (Complete) data for LEVOTHYROXINE (6 total), please visit the HSDB record page.

/BOXED WARNING/ 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. Larger doses may produce serious or even life threatening manifestations of toxicity.|/BOXED WARNING/ WARNING: Thyroid hormones, including Synthroid, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.|Excessive bolus dosing of Levothyroxine Sodium for Injection (greater than 500 ug) 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 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.|Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of thyroid hormones in children. However, caution is necessary in interpreting results of thyroid function tests in neonates, because serum T4 concentrations are transiently elevated and serum T4 concentrations are transiently low, and the infant pituitary is relatively insensitive to the negative feedback effect of thyroid hormones. /Thyroid hormones/|For more Drug Warnings (Complete) data for LEVOTHYROXINE (17 total), please visit the HSDB record page.

Oral levothyroxine is a synthetic hormone that exerts the same physiologic effect as endogenous T₄, thereby maintaining normal T₄ levels when a deficiency is present. Levothyroxine has a narrow therapeutic index and is titrated to maintain a euthyroid state with TSH (thyroid stimulating hormone) within a therapeutic range of 0.4–4.0 mIU/L. Over- or under-treatment with levothyroxine may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function and glucose and lipid metabolism. The dose of levothyroxine should be titrated slowly and carefully and patients should be monitored for their response to titration to avoid these effects. TSH levels should be monitored at least yearly to avoid over-treating with levothyroxine which can result in hyperthyroidism (TSH <0.1mIU/L) and symptoms of increased heart rate, diarrhea, tremor, hypercalcemia, and weakness to name a few. As many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status, over-treatment with levothyroxine may result in increases in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. In populations with any cardiac concerns, levothyroxine should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease. Patients receiving concomitant levothyroxine and sympathomimetic agents should be monitored for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the levothyroxine dose or withhold for one week and restart at a lower dose. Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase and suppressed serum parathyroid hormone levels. Administer the minimum dose of levothyroxine that achieves the desired clinical and biochemical response to mitigate this risk. Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing or discontinuing levothyroxine.

Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80% with the majority of the levothyroxine dose absorbed from the jejunum and upper ileum. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans, milk, and dietary fiber. Absorption may also decrease with age. In addition, many drugs affect T4 absorption including bile acide sequestrants, sucralfate, proton pump inhibitors, and minerals such as calcium (including in yogurt and milk products), magnesium, iron, and aluminum supplements. To prevent the formation of insoluble chelates, levothyroxine should generally be taken on an empty stomach at least 2 hours before a meal and separated by at least 4 hours from any interacting agents.|Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T₄ is eliminated in the stool. Urinary excretion of T₄ decreases with age.|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 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. Thyroid hormones do not readily cross the placental barrier.|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.|Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of Synthroid tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybean infant formula. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption.|Levothyroxine is variably absorbed from the GI tract (range: 40-80%). In animals, levothyroxine is absorbed in the proximal and middle jejunum; the drug is not absorbed from the stomach or distal colon and little, if any, absorption occurs in the duodenum. Studies in humans indicate that levothyroxine is absorbed from the jejunum and ileum and some absorption also occurs in the duodenum. The degree of absorption of levothyroxine from the GI tract depends on the product formulation and type of intestinal contents, including plasma protein and soluble dietary factors that may bind thyroid hormone and make it unavailable for diffusion. In addition, concurrent oral administration of infant soybean formula, soybean flour, cotton seed meal, walnuts, foods containing large amounts of fiber, ferrous sulfate, antacids, sucralfate, calcium carbonate, cation-exchange resins (e.g., sodium polystyrene sulfonate), simethicone, or bile acid sequestrants may decrease absorption of levothyroxine. The extent of levothyroxine absorption is increased in the fasting state and decreased in malabsorption states (e.g., sprue); absorption also may decrease with age.|For more Absorption, Distribution and Excretion (Complete) data for LEVOTHYROXINE (7 total), please visit the HSDB record page.

Approximately 70% of secreted T₄ is deiodinated to equal amounts of T₃ and reverse triiodothyronine (rT₃), which is calorigenically inactive. T₄ is slowly eliminated through its major metabolic pathway to T₃ via sequential deiodination, where approximately 80% of circulating T₃ is derived from peripheral T₄. 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. Elimination of T₄ and T₃ involves hepatic conjugation to glucuronic and sulfuric acids. The hormones undergo enterohepatic circulation as conjugates are hydrolyzed in the intestine and reabsorbed. Conjugated compounds that reach the colon are hydrolyzed and eliminated as free compounds in the feces. Other minor T₄ metabolites have been identified.|Yields l-tyrosine in rabbit, in rat /From table/|Yields 3,3',5-triiodo-L-thyronine in man, rat, dog, rabbit. /From table/|Yields l-thyroxine-4'-beta-d-glucuronide in dog, in man, in rat. Yields l-thyroxine-4'-sulfate in dog. /From table/|Yields 3,3',5,5'-tetraiodothyropyruvic acid in rat. Yields l-thyronine in rat. /From table/|Yields 3,3'-diiodo-l-thyronine in dog. Yields 3,3',5,5'-tetraiodothyroacetic acid in man, in rat. /From table/

T₄ half-life is 6 to 7 days. T₃ half-life is 1 to 2 days.|In dogs orally administered levothyroxine has relatively ... short elimination half life when compared to humans. ... The serum half life is approximately 12-16 hours.|The usual plasma half-lives of thyroxine and triiodothyronine are 6-7 days and approximately 1-2 days, respectively. The plasma half-lives of thyroxine and triiodothyronine are decreased in patients with hyperthyroidism and increased in those with hypothyroidism.

Levothyroxine is a synthetically prepared levo-isomer of the thyroid hormone thyroxine (T₄, a tetra-iodinated tyrosine derivative) that acts as a replacement in deficiency syndromes such as hypothyroidism. T₄ is the major hormone secreted from the thyroid gland and is chemically identical to the naturally secreted T₄: it increases metabolic rate, decreases thyroid-stimulating hormone (TSH) production from the anterior lobe of the pituitary gland, and, in peripheral tissues, is converted to T₃. Thyroxine is released from its precursor protein thyroglobulin through proteolysis and secreted into the blood where is it then peripherally deiodinated to form triiodothyronine (T₃) which exerts a broad spectrum of stimulatory effects on cell metabolism. T₄ and T₃ have a relative potency of ~1:4. Thyroid hormone increases the metabolic rate of cells of all tissues in the body. In the fetus and newborn, thyroid hormone is important for the growth and development of all tissues including bones and the brain. In adults, thyroid hormone helps to maintain brain function, food metabolism, and body temperature, among other effects. The symptoms of thyroid deficiency relieved by levothyroxine include slow speech, lack of energy, weight gain, hair loss, dry thick skin and unusual sensitivity to cold. The thyroid hormones have been shown to exert both genomic and non-genomic effects. They exert their genomic effects by diffusing into the cell nucleus and binding to thyroid hormone receptors in DNA regions called thyroid hormone response elements (TREs) near genes. This complex of T₄, T₃, DNA, and other coregulatory proteins causes a conformational change and a resulting shift in transcriptional regulation of nearby genes, synthesis of messenger RNA, and cytoplasmic protein production. For example, in cardiac tissues T₃ has been shown to regulate the genes for α- and β-myosin heavy chains, production of the sarcoplasmic reticulum proteins calcium-activated ATPase (Ca2+-ATPase) and phospholamban, β-adrenergic receptors, guanine-nucleotide regulatory proteins, and adenylyl cyclase types V and VI as well as several plasma-membrane ion transporters, such as Na+/K+–ATPase, Na+/Ca2+ exchanger, and voltage-gated potassium channels, including Kv1.5, Kv4.2, and Kv4.3. As a result, many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status. The non-genomic actions of the thyroid hormones have been shown to occur through binding to a plasma membrane receptor integrin aVb3 at the Arg-Gly-Asp recognition site. From the cell-surface, T₄ binding to integrin results in down-stream effects including activation of mitogen-activated protein kinase (MAPK; ERK1/2) and causes subsequent effects on cellular/nuclear events including angiogenesis and tumor cell proliferation.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat seizures, hyperthermia, hypotension, and arrhythmias if they occur. 3. Repeated evaluation over several days is recommended after large T4 or combined ingestions because serious symptoms may be delayed. 4. Most patients will suffer no serious toxicity or will recover with simple supportive care. /Thyroid hormone/|For more Antidote and Emergency Treatment (Complete) data for LEVOTHYROXINE (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ The signs and symptoms of overdosage are those of hyperthyroidism. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported.|/CASE REPORTS/ There is currently little literature pertaining to levothyroxine overdose apart from minor or accidental overdoses in the pediatric population. In particular, there is little information available on how to confidently differentiate levothyroxine overdose from endogenous causes of thyrotoxicosis when there is no history available at the time of assessment. We report a levothyroxine (15,800 ug) and citalopram (2,460 mg) overdose in a 55-year-old woman presenting with seizure and tachycardia in which the diagnosis was not initially suspected. Clinical data, including a long history of treated hypothyroidism and lack of a goiter; and biochemical findings, such as an incompletely suppressed thyroid-stimulating hormone (TSH) level, despite a markedly elevated free thyroxine level (FT4), a normal sex hormone-binding globulin level at baseline, and an undetectable thyroglobulin, supported the diagnosis of thyrotoxicosis due to a massive exogenous thyroid hormone overdose. Treatment was given to decrease free triiodothyronine (FT3) conversion and increase thyroid hormone clearance with dexamethasone and cholestyramine. The patient made a full recovery. Levothyroxine overdose can result in subtle symptoms and signs clinically, even when in massive quantities. This can make diagnosis challenging. Biochemical features, such as the pattern of thyroid hormone elevation and thyroglobulin levels, help differentiate exogenous thyroid hormone overdose from endogenous causes of thyrotoxicosis.|/CASE REPORTS/ Exposure to thyroid products is common, but acute poisonings in adults are rare. Most cases of severe toxicity are related to prolonged, repeated exposure (either inadvertent or deliberate abuse). There are a few reports of toxicity in children following large (greater than 10 mg) single ingestions. Expect significant toxicity in children and adults who have ingested more than 2 to 4 mg of levothyroxine. However, in comorbid elderly patients, the threshold may be lower. In this paper we present acute overdose of levothyroxine in nine adult patients (aged 21-44 years; mean--30.5 years); ingested doses were from 1.2 mg to 15 mg (mean--6.5 mg). Only in three cases (ingested doses were 5.6; 8.0 and 15 mg) minor and mild clinical symptoms were observed and pharmacological treatment was necessary. No severe symptoms were observed in our group. Asymptomatic clinical course in patients who ingested more than 3 mg of levothyroxine probably was related to coingestion of benzodiazepins, beta-blockers, ACE inhibitors and ethanol. Serum free triiodothyronine (T3) level of 20 pg/ml (normal, 4.1 pg/ml) was reported following an overdose of 15 mg levothyroxine in day five. Normalization was observed in day eleven.|/CASE REPORTS/ We describe the course of a toddler who ingested a massive amount of levothyroxine and review treatment options for such overdoses. A 2 1/2-year-old boy presented shortly after an ingestion of up to 7.6 mg of levothyroxine (potentially as much as 700 ug/kg). He was initially asymptomatic, treated with oral charcoal 1 g/kg, and discharged home from the emergency department after a few hours. He returned approximately 24 hours later with a temperature of 38.5 °C, heart rate of 163 beats per minute, respiratory rate of 30 breaths per minute, and blood pressure of 136/70 mm Hg. He had a slightly decreased appetite and no signs or symptoms of infection. He was admitted to hospital and treated with oral acetaminophen. The initial free thyroxine (T4) was > 100 pmol/L and free triiodothyronine (T3) was 35.3 pmol/L. The patient had desquamation of the palms and soles, hair loss, and irritability during the month following the ingestion. Resolution of the elevated free T4 occurred by 12 days post-ingestion and normalization of the thyroid-stimulating hormone by 7 weeks post-ingestion. There were no long-term sequelae. Levothyroxine overdose can result in significant complications, including seizures and arrhythmias, both of which should be monitored for. However, as our case illustrates, massive ingestion of levothyroxine in children typically follows a benign course.|For more Human Toxicity Excerpts (Complete) data for LEVOTHYROXINE (12 total), please visit the HSDB record page.

3,5,3',5'-Tetraiodothyronine

Levothyroxine Sodium Powder (Veterinary): 0.22% (1 g of T4 in 454 g of powder): One level teaspoonful contains 12 mg of T4. Available in 1 lb and 10 lb containers; many trade name products may be available and include: Equine Thyroid Supplement, Thyrozine Powder, Levoxine Powder; Thyro-L, Throxine-L Powder, Thyrosyn Powder, Thyrokare Powder; (Rx). Labeled for use in horses.|Levothyroxine Oral Solution: 1 mg/mL in 30 mL bottles: Leventa Oral Solution; (Rx). Labeled for use in dogs.|Levothyroxine Sodium tablets Chewable (Veterinary): 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg; Products that may be available include: Canine Thyroid Chewable Tablets, Nutrived T-4 Chewable Tablets, Thyromed Chewable Tablets; (Rx). Labeled for use in dogs.|Levothyroxine Sodium Tablets: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg and 1 mg; many trade name products may be available and include: Soloxine, Levosyn, Thyro_tabs, Thyrosyn, Thyrosine-L Tablets, Thyrozine, Thyrokare, generic; (Rx). Labeled for use in dogs.|Table: Levothyroxine Sodium Preparations [Table#4444]

L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-: ACTIVE|Top 200 drug - Syntheroid|Synthroid is synthetic levothyroxine and is identical to that produced in the human thyroid gland.

ACTIVE INGREDIENTS WERE ISOLATED & ANALYZED SPECTROPHOTOMETRICALLY FOLLOWING REDN TO TRIIODIDE ION. METHOD MAY BE APPLIED TO DOSAGE LEVELS AS LOW AS 5 UG.|THYROXINE IS DETECTED BY TLC & IODOTHYRONINE BY LIQ CHROMATOGRAPHY.

2-(4-HYDROXYBENZENEAZO)BENZOIC ACID INTERACTS WITH SERUM ALBUMIN TO GIVE CHARACTERISTIC PHOTOMETRIC PEAKS & PROVIDES BASIS FOR ASSAY TO MEASURE AMT BOUND & FREED.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients