Dist. by

FOREST PHARMACEUTICALS, INC.

A Subsidiary of Forest Laboratories, Inc.

St. Louis, MO 63045

LEVOTHROID TABLETS (levothyroxine sodium tablets, USP) provide crystalline sodium levothyroxine (T ₄ ), a potent thyroid hormone, in twelve different strengths to permit easy, convenient dosage adjustment.

The structural formula for sodium levothyroxine as contained in Levothroid Tablets is:

Sodium L-3, 3', 5, 5'-tetraiodothyronine

Inactive Ingredients (Levothroid Tablets): Lactose Monohydrate, NF; Magnesium Stearate, NF; Colloidal Silicon Dioxide, NF; Microcrystalline Cellulose, NF.

The following are the color additives listed by strength:

The major thyroid hormones are L-thyroxine (T ₄ ) and L-triiodothyronine (T ₃ ). The amounts of T ₄ and T ₃ released into the circulation from the normally functioning thyroid gland are regulated by the amount of thyrotropin (TSH) secreted from the anterior pituitary gland. TSH secretion is in turn regulated by the levels of circulating T ₄ and T ₃ and by secretion of thyrotropin releasing factor (TRH) from the hypothalamus. Recognition of this complex feedback system is important in the diagnosis and treatment of thyroid dysfunction.

The principal effect of exogenous thyroid hormone is to increase the metabolic rate of body tissues.

The thyroid hormones are also concerned with growth and differentiation of tissues. In deficiency states in the young there is retardation of growth and failure of maturation of the skeletal and other body systems, especially in failure of ossification in the epiphyses and in the growth and development of the brain.

The precise mechanism of action by which thyroid hormones affect thermogenesis and cellular growth and differentiation is not known. It is recognized that these physiologic effects are mediated at the cellular level primarily by T ₃ , a large part of which is derived from T ₄ by deiodination in the peripheral tissues. Thyroxine (T ₄ ) is the major component of normal secretions of the thyroid gland and is thus the primary determinant of normal thyroid function.

Levothroid tablets are rapidly absorbed after oral administration. Maximum observed plasma concentrations are reached within 1.5 to 3 hours of oral dosing. Following a single dose of 600 mcg or Levothroid to healthy volunteers, peak plasma concentrations of T ₄ averaged 12.2 mcg/dL, where as T ₃ plasma levels were indistinguishable from the baseline values. Peak plasma concentration of T ₄ increased proportionally with increases in dose from 50 to 300 mcg.

Depending on other factors, absorption has varied from 48 to 79 percent of the administered dose. Fasting increases absorption. Malabsorption syndromes, as well as dietary factors, (children's soybean formula, concomitant use of anionic exchange resins such as cholestyramine) cause excessive fecal loss.

More than 99 percent of circulating hormones are bound to serum proteins, including thyroid-binding globulin (TBg), thyroid-binding prealbumin (TBPA), and albumin (TBa), whose capacities and affinities vary for the hormones. L-thyroxine displays greater binding affinity than L-triiodothyronine, both in the circulation and at the cellular level, which explains its longer duration of action. The half-life of T ₄ in normal plasma is 6-7 days while that of T ₃ is about 1 day. The plasma half-lives of T ₄ and T ₃ are decreased in hyperthyroidism and increased in hypothyroidism.

Levothroid Tablets (levothyroxine sodium tablets, USP) are indicated as replacement or substitution therapy for diminished or absent thyroid function (e.g., cretinism, myxedema, non-toxic goiter or hypothyroidism generally, including the hypothyroid state in children, in pregnancy and in the elderly) resulting from functional deficiency, primary atrophy, from partial or complete absence of the gland or from the effects of surgery, radiation or antithyroid agents. Therapy must be maintained continuously to control the symptoms of hypothyroidism.

It may also be used to suppress the secretion of thyrotropin (TSH), action which may be beneficial in simple nonendemic goiter and in chronic lymphocytic thyroiditis. This may cause a reduction in the goiter size. In addition, Levothroid, in conjunction with surgery and radioactive iodine therapy, is indicated as a pituitary TSH suppressant in the management of TSH-dependent well-differentiated papillary or follicular carcinoma of the thyroid.

Thyroid hormone drugs are indicated as a diagnostic agent in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy.

Thyroid hormones may also be used with antithyroid drugs to treat thyrotoxicosis. This combination has been used to prevent goitrogenesis and hypothyroidism.

CONTRAINDICATIONS

Levothroid Tablets administration is contraindicated in untreated thyrotoxicosis, in acute myocardial infarction, and apparent hypersensitivity to thyroid hormones. There is no well-documented evidence of allergic reactions to thyroid hormones. Levothroid Tablets are contraindicated in the presence of uncorrected adrenal insufficiency because it increases the tissue demands for adrenocortical hormones and may cause an acute adrenal crisis in such patients. (See PRECAUTIONS ).

The use of thyroid hormones in the therapy of obesity, alone or combined with other drugs, is unjustified and has been shown to be ineffective. Neither is their use justified for the treatment of male or female infertility unless this condition is accompanied by hypothyroidism.

PRECAUTIONS

GENERAL--Levothroid Tablets should be used with caution in patients with cardiovascular disease, including hypertension. The development of chest pain or other aggravation of cardiovascular disease will require a decrease in dosage.

Thyroid hormone therapy in patients with concomitant diabetes mellitus or diabetes insipidus or adrenal cortical insufficiency aggravates the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases are required. The therapy of myxedema coma requires simultaneous administration of glucocorticoids. (See DOSAGE AND ADMINISTRATION ).

In infants, excessive doses of thyroid hormone preparations may produce craniosynostosis.

INFORMATION FOR THE PATIENT-- Patients on thyroid preparations and parents of children on thyroid therapy should be informed that:

1. Replacement therapy is to be taken essentially for life, with the exception of cases of transient hypothyroidism, usually associated with thyroiditis, and in those patients receiving a therapeutic trial of the drug.
2. They should immediately report during the course of therapy any signs or symptoms of thyroid hormone toxicity, e.g., chest pain, increased pulse rate, palpitations, excessive sweating, heat intolerance, nervousness, or any other unusual event.
3. In case of concomitant diabetes mellitus, the daily dosage of antidiabetic medication may need readjustment as thyroid hormone replacement is achieved. If thyroid medication is stopped, a downward readjustment of the dosage of insulin or oral hypoglycemic agent may be necessary to avoid hypoglycemia. At all times, close monitoring of urinary glucose levels is mandatory in such patients.
4. In case of concomitant oral anticoagulant therapy, the prothrombin time should be measured frequently to determine if the dosage of oral anticoagulants is to be readjusted.
5. Partial loss of hair may be experienced by children in the first few months of thyroid therapy, but this is usually a transient phenomenon and later recovery is usually the rule.

LABORATORY TESTS-- The patient' response to thyroid replacement may be followed by laboratory tests such as serum thyroxine (T ₄ ), serum triiodothyronine (T ₃ ), free thyroxine index and thyroid stimulating hormone (TSH) blood levels. In hypopituitarism, the serum TSH level is not usually useful and monitoring should be done with measurement of serum total or free T ₄ . In euthyroid goiter patients or those with thyroid cancer the serum TSH should be suppressed below the reference range.

DRUG INTERACTIONS --Antidiabetic Agents--In patients with diabetes mellitus, addition of thyroid hormone therapy may cause an increase in the required dosage of insulin or oral hypoglycemic agents. Conversely, decreasing the dose of thyroid hormone may possibly cause hypoglycemic reactions if the dosage of insulin or oral hypoglycemic agents is not adjusted.

Anticoagulants--Thyroid replacement may potentiate anticoagulant effects with agents such as warfarin or bishydroxycoumarin and reduction of one-third in anticoagulant dosage should be undertaken upon initiation of Levothroid Tablets therapy. Subsequent anticoagulant dosage adjustment should be made on the basis of frequent prothrombin determinations.

Sympathetic interactions--Injection of epinephrine in patients with coronary artery disease may precipitate an episode of coronary insufficiency. This may be enhanced in patients receiving thyroid preparations. Careful observation is required if catecholamines are administered to patients in this category.

Cholestyramine or colestipol binds both T ₄ and T ₃ in the intestine, thus impairing absorption of these thyroid hormones. In vitro   studies indicate that the binding is not easily removed. Therefore, four to five hours should elapse between administration of cholestyramine or colestipol and thyroid hormones.

Estrogens tend to increase serum thyroxine-binding globulin (TBg). In a patient with a non-functioning thyroid gland who is receiving thyroid replacement therapy, free levothyroxine may be decreased when estrogens are started thus increasing thyroid requirements. However, if the patient' thyroid gland has sufficient function the decreased free thyroxine will result in a compensatory increase in thyroxine output by the thyroid. Therefore, patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their thyroxine dose if estrogens or estrogen-containing oral contraceptives are given.

DRUG/LABORATORY TEST INTERACTIONS-- The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroid hormone therapy: androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-containing preparations, and the numerous preparations containing salicylates. In some instances, for example, the use of androgens, estrogens, or oral contraceptives, a patient' thyroid status may be affected and monitoring with serum TSH measurements may be suggested.

1. Changes in TBg concentration should be taken into consideration in the interpretation of T ₄ and T ₃ values. In such cases, the unbound (free) hormone should be measured. Pregnancy, estrogens, and estrogen-containing oral contraceptives increase TBg concentrations. TBg may also be increased during infectious hepatitis. Decreases in TBg concentrations are observed in nephrosis, acromegaly, and after androgen or corticosteroid therapy. Familial hyper- or hypo-thyroxine-binding-globulinemias have been described. The incidence of TBg deficiency approximates 1 in 9000. The binding of thyroxine by thyroid-binding prealbumin (TBPA) is inhibited by salicylates.
2. Medical or dietary iodine interferes with all in vivo   tests of radioiodine uptake, producing low uptakes which may not be reflective of a true decrease in hormone synthesis.
3. The persistence of clinical and laboratory evidence of hypothyroidism in spite of adequate dosage replacement indicates either poor patient compliance, poor absorption, excessive fecal loss, or inactivity of the preparation. Intracellular resistance to thyroid hormone is quite rare.

CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY-- A reportedly apparent association between prolonged thyroid therapy and breast cancer has not been confirmed and patients on thyroxine for established indications should not discontinue therapy. No confirmatory long-term studies in animals have been performed to evaluate carcinogenic potential, mutagenicity, or impairment of fertility in either males or females.

PREGNANCY-CATEGORY A-- Thyroid hormones do not readily cross the placental barrier. The clinical experience to date does not indicate any adverse effect on fetuses when thyroid hormones are administered to pregnant women. On the basis of current knowledge, thyroid replacement therapy to hypothyroid women should not be discontinued during pregnancy, but the requirements for dosage may increase and should not be measured periodically with measurements of serum TSH concentration.

NURSING MOTHERS-- Minimal amounts of thyroid hormones are excreted in human milk. Thyroid hormone is not associated with serious adverse reactions and does not have a known tumorigenic potential. However, caution should be exercised when thyroid is administered to a nursing woman.

GERIATRIC USE-- Sufficient numbers of subjects have been studied to indicate that the administration of levothyroxine to the elderly may require adjustment of dosing or monitoring.

In one study, the average full replacement dose of levothyroxine of 23 elderly (average age 75.5 years) ambulatory patients with primary hypothyroidism was 75% of the mean full replacement dose of 44 younger (average age 48.1 years) patients. In another study, levothyroxine replacement dose in elderly patients (mean age, 66.1 years) was found to be 33% less than that formerly recommended.

The decrease in replacement dose in the elderly may be due to the reduction in the fractional thyroxine degradation rate. The reduction in thyroxine turnover in the elderly may be a function of age-related decline in lean body mass.

Optimal daily levothyroxine dosage may not decline universally in all elderly patients, but be dependent on the etiology of the disorder causing the hypothyroidism. Therefore, it should not be assumed that all elderly patients require smaller maintenance doses of Levothroid than younger patients. At any age, titration of dose to restoration of euthyroidism should be based on the clinical response of the patient and normalization of serum TSH concentration.

PEDIATRIC USE-- The diagnosis and institution of therapy for cretinism should be done as soon after birth as feasible to prevent developmental deficiency. Screening tests for serum T ₄ and TSH will identify this group of newborn patients.

ADVERSE REACTIONS

Patients who are sensitive to lactose may show intolerance to Levothroid Tablets since this substance is used in the manufacture of the product.

Adverse reactions other than those indicative of hyperthyroidism because of therapeutic overdosage, either initially or during the maintenance period, are rare. (See OVERDOSAGE ).

OVERDOSAGE

Excessive dosage of thyroid medication may result in symptoms of hyperthyroidism. Since, however, the effects do not appear at once, the symptoms may not appear for one to three weeks after the dosage regimen is begun. The most common signs and symptoms of overdosage are menstrual changes, increase in blood pressure, increase in appetite, weight loss, palpitation, nervousness, diarrhea or abdominal cramps, sweating, tachycardia, cardiac arrhythmias, angina pectoris, tremors, headache, insomnia, intolerance to heat and fever. If symptoms of overdosage appear, discontinue medication for several days and reinstitute treatment at a lower dosage level.

Laboratory tests such as serum T ₄ , and serum T ₃ and the free thyroxine index will be elevated during the period of overdosage.

Complications as a result of the induced hypermetabolic state may include cardiac failure and death due to arrhythmia or failure.

TREATMENT OF OVERDOSAGE-- Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis function is restored in 6 to 8 weeks after thyroid suppression.

Treatment of acute massive thyroid hormone overdosage is aimed at reducing gastrointestinal absorption of the drugs and counteracting central and peripheral effects, mainly those of increased sympathetic activity. Vomiting may be induced initially if further gastrointestinal absorption can reasonably be prevented and barring contraindications such as coma, convulsions, or loss of the gagging reflex. Treatment is symptomatic and supportive. Oxygen may be administered and ventilation maintained. Cardiac glycosides may be indicated if congestive heart failure develops. Measures to control fever, hypoglycemia, or fluid loss should be instituted if needed. Antiadrenergic agents, particularly propranolol, have been used advantageously in the treatment of increased sympathetic activity. Propranolol may be administered intravenously at a dosage of 1 to 3 mg over a 10-minute period or orally, 80 to 160 mg/day, initially, especially when no contraindications exist for its use. Other adjunctive measures may include administration of cholestyramine to interfere with thyroxine absorption, and glucocorticoids to inhibit conversion of T ₄ to T ₃ .

DOSAGE AND ADMINISTRATION

The goal of therapy should be the restoration of euthyroidism as judged by clinical response and confirmed by appropriate laboratory values. In adults with no complicating endocrine or cardiovascular disease, the predicted full maintenance dose may be achieved immediately with adjustments made as indicated by clinical evaluation. The usual maintenance dose of Levothroid Tablets is 100 to 200 mcg.

In patients with known complications or in case of doubt, individual dose titration at 2- to 4-week intervals is recommended. The usual starting dose is 50 mcg with increases of 50 mcg at 2- to 4-week intervals until the patient is euthyroid or symptoms ensue which preclude further dose increase.

In adult myxedema or hypothyroid patients with angina, the starting dose should be 25 mcg with increases at 2- to 4-week intervals of 25 to 50 mcg as determined by clinical response.

Myxedema coma is usually precipitated in the hypothyroid patient of long-standing by intercurrent illness or drugs such as sedatives and anesthetics and should be considered a medical emergency. Therapy should be directed at the correction of electrolyte disturbances and possible infection besides the administration of thyroid hormones. Corticosteroids should be administered routinely. T ₄ and T ₃ may be administered via a nasogastric tube, but the preferred route of administration of both hormones is intravenous. Sodium levothyroxine (T ₄ ) is given at a starting dose of 200-500 mcg (100 mcg/mL given rapidly), and is usually well tolerated, even in the elderly. This initial dose is followed by daily supplements of 100 to 200 mcg given IV. Normal T ₄ levels are achieved in 24 hours followed in 3 days by threefold increase of T ₃ . Oral therapy with Levothroid Tablets should be resumed as soon as the clinical situation has been stabilized and the patient is able to take oral medication.

Pediatric dosage should follow the recommendations summarized in Table I. In infants with congenital hypothyroidism, therapy with full doses should be instituted as soon as the diagnosis has been made. Levothroid Tablets may be given to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount of water (5 to 10 ml), breast milk or formula (non-soybean). The suspension can be given by spoon or dropper. DO NOT STORE THE SUSPENSION FOR ANY PERIOD OF TIME. The crushed tablet may also be sprinkled over a small amount of food, such as cooked cereal or apple sauce. Foods or formulas containing large amounts of iron, soybean, or fiber should not be used to administer Levothroid.

HOW SUPPLIED

Tablets should be stored at controlled room temperature, 59°-86°F (15°-30°C) in capped bottles or unbroken plastic strip packing. Levothroid Tablets should be protected from light and moisture.

Rev. 7/99           03690799

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