Levoxyl^®
(levothyroxine sodium tablets, USP)

—LEVOXYL^® (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 an empirical formula of C₁₅H₁₀I₄N NaO₄· H₂O, molecular weight of 798.86 g/mol (anhydrous), and structural formula as shown:

Microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The following are the coloring additives per tablet strength:

Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyroid-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 physiologic actions of thyroid hormones are produced predominately 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, DOSAGE AND ADMINISTRATION).

Levothyroxine sodium is used for the following indications:

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 (see PRECAUTIONS). LEVOXYL^® is contraindicated in patients with hypersensitivity to any of the inactive ingredients in LEVOXYL^® tablets (see DESCRIPTION, Inactive Ingredients).

Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.

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 (see CONTRAINDICATIONS). If the serum TSH level is not suppressed, LEVOXYL^® 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 has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or under-treatment. These consequences include, among others, effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Many drugs interact with levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response (see Drug Interactions).

Patients should be informed of the following information to aid in the safe and effective use of LEVOXYL^®:

• Notify your physician if you are allergic to any foods or medicines, are pregnant or intend to become pregnant, are breast-feeding or are taking any other medications, including prescription and over-the-counter preparations.
• Notify your physician of any other medical conditions you may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems. Your dose of medications used to control these other conditions may need to be adjusted while you are taking LEVOXYL^®. If you have diabetes, monitor your blood and/or urinary glucose levels as directed by your physician and immediately report any changes to your physician. If you are taking anticoagulants (blood thinners), your clotting status should be checked frequently.
• Use LEVOXYL^® only as prescribed by your physician. Do not discontinue or change the amount you take or how often you take it, unless directed to do so by your physician.
• The levothyroxine in LEVOXYL^® is intended to replace a hormone that is normally produced by your thyroid gland. Generally, replacement therapy is to be taken for life, except in cases of transient hypothyroidism, which is usually associated with an inflammation of the thyroid gland (thyroiditis).
• Take LEVOXYL^® in the morning on an empty stomach, at least one-half hour before eating any food.
•  LEVOXYL^® may rapidly swell and disintegrate resulting in choking, gagging, the tablet getting stuck in your throat or difficulty swallowing. It is very important that you take the tablet with a full glass of water. Most of these problems disappeared when Levoxyl^® tablets were taken with water.
• It may take several weeks before you notice an improvement in your symptoms.
• Notify your physician if you experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event.
• Notify your physician if you become pregnant while taking LEVOXYL^®. It is likely that your dose of LEVOXYL^® will need to be increased while you are pregnant.
• Notify your physician or dentist that you are taking LEVOXYL^® prior to any surgery.
• Partial hair loss may occur rarely during the first few months of LEVOXYL^® therapy, but this is usually temporary.
• LEVOXYL^® should not be used as a primary or adjunctive therapy in a weight control program.
• Keep LEVOXYL^® out of the reach of children. Store LEVOXYL^® away from heat, moisture, and light.

Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to LEVOXYL^®. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and action of other drugs. A uling of drug-thyroidal axis interactions is contained in Table 2.

The ul of drug-thyroidal axis interactions in Table 2 may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware of this fact and should consult appropriate reference sources. (e.g., package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected.

Because of the increased prevalence of cardiovascular disease among the elderly, levothyroxine therapy should not be initiated at the full replacement dose (see WARNINGS,PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage. They include the following:

General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating;

Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia;

Musculoskeletal: tremors, muscle weakness;

Cardiac: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest;

Pulmonary: dyspnea;

GI: diarrhea, vomiting, abdominal cramps;

Dermatologic: hair loss, flushing;

Reproductive: menstrual irregularities, impaired fertility.

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.

Seizures have been reported rarely with the institution of levothyroxine therapy.

Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism.

Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

In addition to the above events, the following have been reported, predominately when Levoxyl^® tablets were not taken with water: choking, gagging, tablet stuck in throat and dysphagia (see Information for Patients).

The signs and symptoms of overdosage are those of hyperthyroidism (see PRECAUTIONS and ADVERSE REACTIONS). In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures have occurred in a child ingesting approximately 20 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

Levothyroxine sodium should be reduced in dose or temporarily discontinued if signs or symptoms of overdosage occur.

The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of LEVOXYL^® that is adequate to achieve these goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated (see WARNINGS and PRECAUTIONS). Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters (see PRECAUTIONS, Laboratory Tests).

The LEVOXYL^® should be taken in the morning on an empty stomach, at least one-half hour before any food is eaten. LEVOXYL^® should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see PRECAUTIONS, Drug Interactions).

LEVOXYL^® should be taken with water (see Informations for Patients and ADVERSE REACTIONS).

Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4–6 weeks.

Caution should be exercised when administering LEVOXYL^® to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS).

Levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight decreasing with age (see TABLE 3). However, in children with chronic or severe hypothyroidism, an initial dose of 25 mcg/day of levothyroxine sodium is recommended with increments of 25 mcg every 2–4 weeks until the desired effect is achieved.

Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the full recommended replacement dose until the full recommended replacement dose is reached.

— LEVOXYL^®(levothyroxine sodium tablets, USP) are supplied as oval, color-coded, potency marked tablets in 12 strengths:

20°–25°C (68°–77°F) with excursions permitted between 15°–30°C (59°–86°F).
Meets USP Dissolution Tests 1 and 2.

Rx ONLY

MANUFACTURER
JONES PHARMA INCORPORATED
(A wholly owned subsidiary of King Pharmaceuticals, Inc.)
Bristol, VA 24201

Prescribing Information as of May 2004