Levothyroxine Sodium for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Levothyroxine Sodium for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Hypothyroidism, Post-Thyroidectomy (Hypothyroidism, After Thyroid Removal), Hypothyroidism, After Thyroid Removal (Hypothyroidism, Post-Thyroidectomy), Hypothyroidism (Underactive Thyroid), Myxedema Coma
Class: Thyroid drugs
Form: Liquid solution, Intramuscular (IM), Intravenous (IV)
Ingredients: Anhydrous levothyroxine sodium (levothyroxine), mannitol, sodium phosphate, dibasic heptahydrate, sodium hydroxide.

Pharmaceutical Information

Drug Substance

Sodium Levothyroxine is a physiologically active material being the levo-isomer of thyroxine.

Proper Name: Sodium Levothyroxine (L-T4, Na)
Chemical Name: USP: (1) L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-
         diiodo-, monosodium salt
         (2) Monosodium L-thyroxine hydrate
EP: sodium(2S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-
       3, 5-dioodophenyl] propanoate
Molecular Formula and Molecular Mass: C15H10I4NNaO4 • xH2O
798.85 g/mol (anhydrous)
Structural Formula:
Physicochemical Properties: Off-white to slightly brownish-yellow powder or fine,
faintly coloured crystalline powder
Solubility: Very slightly soluble in water
Slightly soluble in ethanol
Soluble in alkali hydroxide solutions
Solventg/100 mL
H2O0.14
95%ethanol 0.3, 0.4
alkali hydroxidessoluble
chloroformalmost insoluble
ethyl etheralmost insoluble
pH 7.4 buffer0.022 - 0.044
Melting point: IsomerMelting Range (°C)
L-T4233 - 235 (decomp)
L-T4235 - 236 (decomp)
D-T4237 (decomp)
L-T4236 (corr)
pKa: The apparent pKa of the phenolic hydroxyl, carboxyl and amino
functions has been reported:
FunctionpKapKaa
carboxyl2.23.832
phenolic hydroxyl6.78.085
amino10.19.141

a In 75% dimethylsulfoxide-water and 0.1 M KNO3

Titrant: potentiometric with sodium hydroxide

Clinical Trials

Thyroxine therapy is given to replace thyroid hormone secretion when it is deficient (hypothyroidism).

Studies of the effect of thyroxine replacement therapy on bone mineral density have given conflicting results; the reductions in bone mass reported by some have prompted recommendations that prescribed doses of thyroxine be reduced. The long-term effect of thyroxine treatment was examined in a large homogenous group of patients, all having undergone thyroidectomy for differentiated thyroid cancer with no history of other thyroid disorders.

Despite long-term thyroxine therapy [mean duration 7.9 (range 1 - 19) years] at doses [mean 191 (SD 50) μg/day] that resulted in higher serum thyroxine and lower serum thyrotropin concentrations than in the controls, the patients showed no evidence of lower bone mineral density than the controls at any site. Nor was bone mineral density correlated with dose, duration of therapy or cumulative intake, or with tests of thyroid function.

In a study to evaluate the effects of pregnancy on thyroxine requirements, a retrospective review of 12 women receiving treatment for primary hypothyroidism before, during, and after pregnancy was conducted.

In all patients, the serum thyrotropin level increased during pregnancy. Because of high thyrotropin levels, the thyroxine dose was increased in 9 of the 12 patients. The results indicate that the need for thyroxine increases in many women with primary hypothyroidism when they are pregnant.

The longitudinal response in 43 infants with congenital primary hypothyroidism during the first year of levothyroxine therapy was evaluated. Diagnosis was confirmed by serum thyroid hormone measurements by 4 weeks of age in 38 infants and between 40 and 80 days of age in the remainder.

Levothyroxine therapy, at an average dose of 10 to 14 μg/kg/day, was begun immediately after diagnosis, and serum concentrations of total thyroxine, triiodothyronine, reverse triiodothyronine and TSH were determined serially. Serum concentration of total and free thyroxine became normal within 1 week of the start of therapy in all groups. Despite a similarly mild degree of hypothyroidism at diagnosis in infants with dyshormonogenesis or with ectopia or hypoplasia, those with dyshormonogenesis had a more sensitive response to initial thyroid hormone replacement therapy than did patients with thyroid dysgenesis, as judged by levothyroxine dose and TSH suppression. It was concluded that prompt restoration of clinical and biochemical euthyroidism during early infancy with doses of levothyroxine between 10 to 14 μg/kg/day was a safe and effective method of therapy for children with congenital hypothyroidism.

Detailed Pharmacology

Pharmacodynamic Properties

The normal thyroid gland secretes sufficient amounts of the thyroid hormones, triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine), to maintain normal growth and development, normal body temperature, and normal energy levels. These hormones contain 59% and 65%, respectively, of iodine as an essential part of the molecule. Nearly all of iodide (I-) intake is via the gastrointestinal tract from food, water, or medication. This ingested iodide is rapidly absorbed and enters an extracellular fluid pool. The thyroid gland removes about 75 μg a day from this pool for hormone secretion, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the thyroid is diminished.

Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that convert it into active thyroid hormone. The first step is the transport of iodide into the thyroid gland, called iodide trapping. Iodide is then oxidized by thyroidal peroxidase to iodine, in which form it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine and diiodotyrosine. This process is called iodide organification. Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked by thioamide drugs. Two molecules of diiodotyrosine combine within the thyroglobulin molecule to form I -thyroxine (T4). One molecule of monoiodotyrosine and one molecule of diiodotyrosine combine to form T3 . In addition to thyroglobulin, other proteins within the gland may be iodinated, but these iodoproteins do not have hormonal activity. Thyroid hormones are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The colloid droplets of thyroglobulin merge with lysosomes containing proteolytic enzymes, which hydrolyze thyroglobulin and release T4 and T3. The monoiodotyrosine and diiodotyrosine are deiodinated within the gland, and the iodine is reutilized. In addition to T4 and T3, small amounts of thyroglobulin, tyrosine and iodide are secreted. This process of proteolysis is also blocked by high levels of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thyroxine. Most of the T3 circulating in the blood is derived from peripheral metabolism of thyroxine.

The mechanisms by which thyroid hormones exert their physiologic action are not well understood. Free forms of thyroid hormones T4 and T3, dissociated from thyroid binding proteins, enter the cell by diffusion or possibly by active transport. Within the cell, T4 is converted to T3. T3 enters the nucleus and binds to a T3 receptor protein.

Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA and subsequent protein synthesis.

Large numbers of thyroid hormone receptors are found in most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine). The brain, which lacks an anabolic response to T3, contains an intermediate number of receptors. The number of receptors may be altered to preserve body homeostasis.

Some of the widespread effects of thyroid hormones in the body are secondary to stimulation of oxygen consumption, although the hormones also affect growth and development in mammals, help regulate lipid metabolism, and increase the absorption of carbohydrates from the intestine.

Thyroid hormone is critical for nervous, skeletal, and reproductive tissues. Its effects depend upon protein synthesis as well as potentiation of the secretion and action of growth hormone. Thyroid deprivation in early life results in irreversible mental retardation and dwarfism.

Thyroid hormone has a strong influence upon various aspects of renal function. An excess of L-thyroxine or L-triiodothyronine is accomplished by a marked increase in the rate of renal plasma flow (RPF) and glomerular filtration rate (GFR). Moreover, considerable stimulation of the energy consuming epithelial transport of glucose, PAH, trypan blue, and sodium in the proximal tubule can be observed. The upper part of the nephron shows cellular hypertrophy and hyperplasia, and activation of numerous enzymes and increased oxygen consumption. A diuretic response is seen in man and other species, such as rabbits.

In several studies, it has been demonstrated that thyroid hormone treatment also leads to an improvement of renal function in rabbits with severe mercury-induced tubular lesions, as well as in patients with manifest acute renal failure. In another study, male albino rats, following mercury-induced acute tubular lesions, showed marked recovery during L-thyroxine therapy. Treatment initiated immediately totally inhibited the early polyuria noted in control animals. Urinary volume immediately increased after termination of thyroid hormone administration in a similar pattern to that observed in normal rats only treated with L-thyroxine.

Pharmacokinetic Properties and Bioavailability

Few clinical studies have evaluated the kinetics of orally administered thyroid hormones. In animals, the most active sites of absorption appear to be the proximal and mid-jejunum. T4 is not absorbed from the stomach and little, if any, drug is absorbed from the duodenum. There seems to be no absorption of T4 from the distal colon in animals. A number of human studies have confirmed the importance of an intact jejunum and ileum for T4 absorption and have shown some absorption from the duodenum.

Studies involving radioiodinated T4 fecal tracer excretion methods, equilibration, and AUC methods have shown that absorption varies from 48 to 80% of the administered dose. The extent of absorption is increased in the fasting state and decreased in malabsorption syndromes, such as sprue. Absorption may also decrease with age. The degree of T4 absorption is dependent on the product formulation as well as on the character of the intestinal contents, including plasma protein and soluble dietary factors, which bind thyroid hormone making it unavailable for diffusion. Decreased absorption may result from administration of infant soybean formula, ferrous sulfate, sodium polystyrene sulfonate, aluminum hydroxide sucralfate, or bile acid sequestrants. T4 absorption following intramuscular administration is variable. Distribution of thyroid hormones in human body tissues and fluids has not been fully elucidated.

More than 99% of circulating hormones are bound to serum proteins, including thyroxine-binding globulin (TBG), thyroxine-binding pre-albumin (TBPA), and albumin (TBA). T4 is more extensively and firmly bound to serum proteins than is T3 . Only unbound thyroid hormone is metabolically active. The higher affinity of TBG and TBPA for T4 partly explains the higher serum levels, slower metabolic clearance, and longer serum half-life of this hormone. Certain drugs and physiologic conditions can alter the binding of thyroid hormones to serum proteins and/or the concentrations of the serum proteins available for thyroid hormone binding. These effects must be considered when interpreting the results of thyroid function tests. (See DRUG INTERACTIONS, Drug-Laboratory Interactions.)

T4 is eliminated slowly from the body, with a half-life of 6 to 7 days. T3 has a half-life of 1 to 2 days. The liver is the major site of degradation for both hormones. T4 and T3 are conjugated with glucuronic and sulfuric acids and excreted in the bile. There is an enterhepatic circulation of thyroid hormones, as they are liberated by hydrolysis in the intestine and reabsorbed. A portion of the conjugated material reaches the colon unchanged, is hydrolyzed there, and is eliminated as free compounds in the feces. In man, approximately 20 to 40% of T4 is eliminated in the stool. About 70% of the T4 secreted daily is deiodonated to yield equal amounts of T3 and rT3. Subsequent deiodination of T3 and rT3 yields multiple forms of diiodothyronine. A number of other minor T4 metabolites have also been identified. Although some of these metabolites have biological activity, their overall contribution to the therapeutic effect of T4 is minimal.

It has been reported that approximately 80% of endogenous T3 is obtained by metabolism of T4 in the liver and kidneys. Exogenously administered T4 may suppress T3 serum levels in healthy individuals.

Toxicology

Repeated-dose Toxicity

Excess thyroid hormone decreases bone mineral density (BMD), a potential problem in managing patients with differentiated thyroid carcinoma and nontoxic goiter who require lifelong TSH-suppressive doses of thyroid hormone. The effect of thyroid hormone excess on vertebral and femoral BMD and the role of hypogonadism in modulating this effect were studied in a rat model. The potential role of calcitonin in preventing thyroid hormone-associated bone loss was also investigated. A total of 40 male Sprague-Dawley rats were divided into four groups. Groups 1 and 2 were orchidectomized; groups 3 and 4 were sham operated. Groups 1 and 3 received 20 :g intraperitoneal L-thyroxine per 100 g body weight daily for 3 weeks; groups 2 and 4 received vehicle IP. Another 40 rats were divided into four groups with groups 1 and 2 receiving L-thyroxine and 3 and 4 receiving calcitonin, 2.5 U per 100 g body weight, subcutaneously for 3 weeks. Bone mineral density of the L4 and 5 and the right femur were measured by dual-energy x-ray absorptiometry at baseline and at the end of the study. Orchidectomy decreased femoral (p < 0.05) but not lumbar BMD. The administration of excess L-Thyroxine decreased femoral (cortical) BMD in both sham operated (p < 0.05) and orchidectomized rats (p < 0.05) without affecting lumbar (trabecular) BMD. Calcitonin increased lumbar BMD in both vehicle (p < 0.001) and L-thyroxine treated rats (p < 0.001). However, calcitonin did not affect femoral BMD in vehicle-treated rats and did not prevent the L-thyroxine-induced femoral bone loss. Serum tartrate-resistant acid phosphatase (TRAP) was increased in the L-thyroxine-treated (p < 0.001) and the orchidectomized (p < 0.05) rats. Calcitonin had no effect on TRAP activity and did not prevent the L-Thyroxine-induced increase in TRAP. Neither excess L-thyroxine nor orchidectomy affect osteocalcin concentrations. Calcitonin decreased serum osteocalcin concentrations, alone (p < 0.05) and in the presence of excess L-thyroxine (p < 0.05). It was concluded that large doses of L-thyroxine administered to the rat preferentially decreased femoral BMD. Short-term hypogonadism decreases femoral but not lumbar BMD and does not make the lumbar spine more susceptible to the potential thyroid hormone-induced bone loss. Calcitonin increases lumbar BMD but does not prevent the thyroid hormone-induced decrease in femoral BMD.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Few published toxicology studies of levothyroxine have been performed to evaluate any carcinogenic potential, mutagenic potential, or impairment of fertility. Synthetic levothyroxine is identical to that produced by the human thyroid gland and so, effects of this nature would not be expected unless administered in excessive doses.