Levothyroxine Sodium (Page 5 of 6)

Acquired Hypothyroidism in Pediatric Patients

Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height.

8.5 Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium tablets at less than the full replacement dose [see Warnings and Precautions (5.1) and Dosage and Administration (2.3)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

10 OVERDOSAGE

The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma and death have been reported. Seizures occurred in a 3-year- old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

Reduce the levothyroxine sodium tablets dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s medical status.

For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

11 DESCRIPTION

Levothyroxine sodium tablets, USP contain synthetic crystalline L-3,3′,5,5′- tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is chemically identical to that produced in the human thyroid gland. Levothyroxine (T4) sodium has an empirical formula of C15H10I4NNaO4 xH2O (where x = 5), molecular weight of 798.86 g/mol (anhydrous) and structural formula as shown:

molecule levothyroxine sodium

Levothyroxine sodium tablets 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 Magnesium Stearate, NF; Microcrystalline Cellulose, NF; Colloidal Silicone Dioxide, NF; and Sodium Starch Glycolate, NF. Each tablet strength meets USP Dissolution Test 2. Table 6 provides a listing of the color additives by tablet strength:

Table 6. Levothyroxine Sodium Tablets Color Additives

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

12 CLINICAL PHARMACOLO GY

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 tablets 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 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 7). 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 7. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone Ratio in Thyroglobulin Biologic Potency t 1/2 (days) Protein Binding (%) a
Levothyroxine (T4) 10 — 20 1 6-7 b 99.96
Liothyronine (T3) 1 4 ≤ 2 99.5
a. Includes TBG, TBPA and TBA b. 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism

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