Prescription Drug Information: Levothyroxine Sodium

LEVOTHYROXINE SODIUM — levothyroxine sodium tablet
Physicians Total Care, Inc.

DESCRIPTION

Levothyroxine sodium tablets, USP contain synthetic crystalline L-3,3’,5,5’-tetraiodothyronine sodium salt [levothyroxine (T4 ) sodium]. Synthetic T4 is identical to that produced in the human thyroid gland. Levothyroxine (T4 ) sodium has a molecular formula of C15 H10 I4 N NaO4 * H2 O, molecular weight of 798.86 g/mol (anhydrous), and structural formula as shown:

Structural Formula
(click image for full-size original)

Inactive Ingredients

Levothyroxine sodium tablets, USP, for oral administration, are available containing 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg or 300 mcg of levothyroxine sodium, USP. In addition, each tablet contains the following inactive ingredients: butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate and sucrose. The following are the coloring additives by tablet strength:

Strength (mcg) Color additive(s)
25FD&C Yellow No. 6 Aluminum Lake
50None
75FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake
88D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake
100D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake
112D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake
125FD&C Blue No. 1 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake
137FD&C Blue No. 2 Aluminum Lake
150FD&C Blue No. 2 Aluminum Lake
175D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake
200FD&C Red No. 40 Aluminum Lake
300D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake

CLINICAL PHARMACOLOGY

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, L-thyroxine (T4 ) and L-triiodothyronine (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 increase.

The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T3 and 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.

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.

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.

Levothyroxine, at doses individualized according to patient response, is effective as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.

Levothyroxine is also effective in the suppression of pituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimoto’s thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropin-dependent well differentiated thyroid cancer (see INDICATIONS AND USAGE, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Pharmacokinetics

Absorption

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 levothyroxine sodium tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 99%. 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 (see PRECAUTIONS: Drug Interactions and Drug-Food Interactions).

Distribution

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 (see PRECAUTIONS: Drug Interactions and Drug-Laboratory Test Interactions). Thyroid hormones do not readily cross the placental barrier (see PRECAUTIONS: Pregnancy).

Metabolism

T4 is slowly eliminated (see Table 1). The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% 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 (rT3 ). T3 and rT3 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 and is eliminated in the feces. Approximately 20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age.

Table 1: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients
Hormone Ratio in Thyroglobulin Biologic Potency t½ (days) Protein Binding (%)
Levothyroxine (T4 )Liothyronine (T3 ) 10 to 201 14 6 to 7 ≤2 99.9699.5

INDICATIONS AND USAGE

Levothyroxine sodium is used for the following indications:

Hypothyroidism

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.

Pituitary TSH Suppression

In the treatment or prevention of various types of euthyroid goiters (see WARNINGS and PRECAUTIONS), including thyroid nodules (see WARNINGS and PRECAUTIONS), subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), multinodular goiter (see WARNINGS and PRECAUTIONS) and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well differentiated thyroid cancer.

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