Levothyroxine Sodium (Page 5 of 8)

11 DESCRIPTION

Levothyroxine sodium tablets, USP are L-thyroxine (T4) and contains synthetic crystalline L-3,3′,5,5′-tetraiodothyronine sodium salt. Synthetic T4 is chemically 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 (anhydrous), and structural formula as shown:

1
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Levothyroxine sodium tablets, USP for oral administration are supplied in the following strengths: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, and 300 mcg. Each levothyroxine sodium tablet contains the inactive ingredients croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and purified water. Each tablet strength meets USP Dissolution Test 2. Table 9 provides a listing of the color additives by tablet strength:

Table 9. Levothyroxine Sodium Tablets, USP Color Additives

Strength (mcg)

Color additive(s)

25

FD&C Yellow No. 6 Aluminum Lake*

50

None

75

FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake

88

FD&C Blue No. 2 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake*

100

D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake*

112

Carmine

125

FD&C Yellow No. 6 Aluminum Lake*, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake

137

FD&C Blue No. 1 Aluminum Lake

150

FD&C Blue No. 2 Aluminum Lake

175

FD&C Blue No. 2 Aluminum Lake, Carmine

200

FD&C Red No. 40 Aluminum Lake

300

FD&C Yellow No. 6 Aluminum Lake*, FD&C Blue No. 1 Aluminum Lake

* Note – FD&C Yellow No. 6 is orange in color.

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 L-thyroxine (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 Pharmacodynamics

Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as endogenous T4, thereby maintaining normal T4 levels when a deficiency is present.

12.3 Pharmacokinetics

Absorption

Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%. The majority of the levothyroxine sodium 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 93%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption [see Drug Interactions (7)].

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 Drug Interactions (7)]. Thyroid hormones do not readily cross the placental barrier [see Use in Specific Populations (8.1)].

Elimination

Metabolism

T4 is slowly eliminated (see Table 10). 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.

Excretion

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 10. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone

Ratio in Thyroglobulin

Biologic Potency

t1/2 (days)

Protein Binding (%)*

Levothyroxine (T4)

10 to 20

1

6 to 7**

99.96

Liothyronine (T3)

1

4

≤ 2

99.5

* Includes TBG, TBPA, and TBA

** 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism

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