LEVOTHROID® (levothyroxine sodium) Tablets, USP contains 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 x H₂O, molecular weight of 798. 86 g/mol (anhydrous), and structural formula as shown:

Inactive Ingredients: Microcrystalline cellulose, calcium phosphate dibasic, povidone and magnesium stearate. The following are the coloring additives per tablet strength.

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.

General Principles

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 LEVOTHROID® 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 guide-lines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters (see PRECAUTIONS, Laboratory Tests).

LEVOTHROID® is administered as a single daily dose, preferably one-half to one hour before breakfast. LEVOTHROID® should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see PRECAUTIONS, DRUG INTERACTIONS).

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 LEVOTHROID® to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS).

Specific Patient Populations

Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete

(see WARNINGS and PRECAUTIONS, Laboratory Tests )

Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 years who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium is approximately 1. 7 mcg/kg/day (e. g. , 100-125 mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium doses greater than 200 mcg/day are seldom required. An inadequate response to daily doses ≥ 300 mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug interactions.

For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at 6-8 week intervals, as needed. The recommended starting dose of levothyrox-ine sodium in elderly patients with cardiac disease is 12. 5-25 mcg/day, with gradual dose increments at 4-6 week intervals. The levothyroxine sodium dose is generally adjusted in 12. 5-25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized. In patients with severe hypothyroidism, the recommended initial levothyroxine sodium dose is 12. 5-25 mcg/day with increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized.

In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the serum free-T₄ level is restored to the upper half of the normal range.

Pediatric Dosage

Congenital or Acquired Hypothyroidism

(see PRECAUTIONS, Laboratory Tests)

General Principles

In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible. Delays in diagnosis and institution of therapy may have deleterious effects on the child's intellectual and physical growth and development.

Undertreatment and overtreatment should be avoided (see PRECAUTIONS, Pediatric Use).

LEVOTHROID® may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. This suspension can be administered by spoon or dropper. DO NOT STORE THE SUSPENSION. Foods that decrease absorption of levothyroxine, such as soybean infant formula, should not be used for administering levothyroxine sodium tablets (see PRECAUTIONS, Drug-Food Interactions).

Newborns

The recommended starting dose of levothyroxine sodium in newborn infants is 10-15 mcg/kg/day. A lower starting dose (e. g. , 25 mcg/day) should be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment. In infants with very low (< 5 mcg/dL) or undetectable serum T₄ concentrations, the recommended initial starting dose is 50 mcg/day of levothy-roxine sodium.

Infants and Children

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.

Table 3: Levothyroxine Sodium Dosing Guidelines for Pediatric Hypothyroidism

Pregnancy

Pregnancy may increase levothyroxine requirements (see Pregnancy).

Subclinical Hypothyroidism

If this condition is treated, a lower levothyroxine sodium dose (e. g. , 1 mcg/kg/day) than that used for full replacement may be adequate to normalize the serum TSH level. Patients who are not treated should be monitored yearly for changes in clinical status and thyroid laboratory parameters.

TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules

The target level for TSH suppression in these conditions has not been established with controlled studies. In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of LEVOTHROID® used for TSH suppression should be individualized based on the specific disease and the patient being treated.

In the treatment of well-differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy. Generally, TSH is suppressed to < 0.1 mU/L, and this usually requires a levothyroxine sodium dose of greater than 2 mcg/kg/day. However, in patients with high-risk tumors, the target level for TSH suppression may be < 0.01 mU/L.

In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target (e. g. , 0.1 to either 0.5 or 1.0 mU/L) than that used for the treatment of thyroid cancer. Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).

Myxedema Coma

Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Therefore, oral thyroid hormone drug products are not recommended to treat this condition. Thyroid hormone drug products formulated for intravenous administration should be administered.

LEVOTHROID® (levothyroxine sodium tablets, USP) are caplet-shaped, color-coded, potency marked tablets and are supplied as follows:

Storage Conditions

Store at 25°C (77°F) with excursions permitted to 15-30°C (59-86°F). Protect from moisture and light.

Manufactured for: Forest Pharmaceuticals, Inc., Subsidiary of Forest Laboratories, Inc.,St. Louis, Missouri, 63045
by: Lloyd Pharmaceutical Division of Lloyd, Inc., Shenandoah, IA 51601
Rev. 09/05 FDA rev date: 03/10/2006

Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage (see PRECAUTIONS and 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;

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

Respiratory: dyspnea;

Gastrointestinal: diarrhea, vomiting, abdominal cramps and elevations in liver function tests;

Dermatologic: hair loss, flushing;

Endocrine: decreased bone mineral density; 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.

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 LEVOTHROID® . In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs. A listing of drug-thyroidal axis interactions is contained in Table 2.

The list 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.

Table 2:Drug-Thyroidal Axis Interactions

Oral anticoagulants

Levothyroxine increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the LEVOTHROID® dose is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see Table 2).

Digitalis glycosides

The therapeutic effects of digitalis glycosides may be reduced by levothyroxine. Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides (see Table 2).

Drug-Food Interactions

Consumption of certain foods may affect levothyroxine absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the GI tract.

Drug-Laboratory Test Interactions

Changes in TBG concentration must be considered when interpreting T₄ and T₃ values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free-T₄ index (FT₄I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or corticosteroid therapy (see also Table 2). Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.

WARNING : Thyroid hormones, including LEVOTHROID® , either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduc-tion. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sym-pathomimetic amines such as those used for their anorectic effects.

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, LEVOTHROID® 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.

General

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).

Effects on bone mineral density

In women, long-term levothyroxine sodium therapy has been associated with increased bone resorption, thereby decreasing bone mineral density, especially in post-menopausal women on greater than replacement doses or in women who are receiving suppressive doses of levothyroxine sodium. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase and suppressed serum parathyroid hormone levels. Therefore, it is recommended that patients receiving levothyroxine sodium be given the minimum dose necessary to achieve the desired clinical and biochemical response.

Patients with underlying cardiovascular disease

Exercise caution when administering levothyroxine to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease. In these patients, levothyroxine therapy should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease (see WARNINGS; PRECAUTIONS, Geriatric Use;and DOSAGE AND ADMINISTRATION). If cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and then cautiously restarted at a lower dose. Overtreatment with levothyroxine sodium may have adverse cardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias. Patients with coronary artery disease who are receiving levothyrox-ine therapy should be monitored closely during surgical procedures, since the possibility of precipitating cardiac arrhythmias may be greater in those treated with levothyroxine. Concomitant administration of levothyroxine and sympathomimetic agents to patients with coronary artery disease may precipitate coronary insufficiency.

Patients with nontoxic diffuse goiter or nodular thyroid disease

Exercise caution when administering levothyroxine to patients with nontoxic diffuse goiter or nodular thyroid disease in order to prevent precipitation of thyrotoxicosis (see WARNINGS). If the serum TSH is already suppressed, levothyrox-ine sodium should not be administered (see CONTRAINDICATIONS).

Associated endocrine disorders

Hypothalamic/pituitary hormone deficiencies

In patients with secondary or tertiary hypothyroidism, additional hypothalamic/pituitary hormone deficiencies should be considered, and, if diagnosed, treated (see PRECAUTIONS, Autoimmune polyglandular syndrome for adrenal insufficiency).

Autoimmune polyglandular syndrome

Occasionally, chronic autoimmune thyroiditis may occur in association with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus. Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of treatment with levothyroxine sodium. Failure to do so may precipitate an acute adrenal crisis when thyroid hormone therapy is initiated, due to increased metabolic clearance of glucocorticoids by thyroid hormone. Patients with diabetes mellitus may require upward adjustments of their antidiabetic therapeutic regimens when treated with levothyroxine (see PRECAUTIONS, DRUG INTERACTIONS).

Other associated medical conditions

Infants with congenital hypothyroidism appear to be at increased risk for other congenital anomalies, with cardiovascular anomalies (pulmonary stenosis, atrial septal defect, and ventricular septal defect) being the most common association.

Laboratory Tests

General

The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation assay sensitivity ≤ 0. 1 mIU/L or third generation assay sensitivity ≤ 0. 01 mIU/L) and measurement of free-T₄.

The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. The choice of laboratory tests depends on various factors including the etiology of the underlying thyroid disease, the presence of concomitant medical conditions, including pregnancy, and the use of concomitant medications (see PRECAUTIONS, DRUG INTERACTIONS and Drug-Laboratory Test Interactions). Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of LEVOTHROID® may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T₄ potency of the drug product.

Adults

In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until nor-malization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage of levothyroxine changed, the serum TSH concentration should be measured after 8-12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6-12 months, depending on the clinical situation, and whenever there is a change in the patient's status. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving LEVOTHROID® (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Pediatrics

In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring both serum TSH (using a sensitive assay) and total- or free-T₄. During the first three years of life, the serum total- or free-T₄ should be maintained at all times in the upper half of the normal range. While the aim of therapy is to also normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid feedback threshold as a result of in utero hypothy-roidism. Failure of the serum T₄ to increase into the upper half of the normal range within 2 weeks of initiation of LEVOTHROID® therapy and/or of the serum TSH to decrease below 20mU/L within 4 weeks should alert the physician to the possibility that the child is not receiving adequate therapy. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of LEVOTHROID® .

The recommended frequency of monitoring of TSH and total- or free-T₄ in children is as follows: at 2 and 4 weeks after the initiation of treatment;every 1-2 months during the first year of life;every 2-3 months between 1 and 3 years of age;and every 3 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T₄ levels, and a physical examination, if indicated, be performed 2 weeks after any change in LEVOTHROID® dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION).

Secondary (pituitary) and tertiary (hypothalamic) hypothyroidism

Adequacy of therapy should be assessed by measuring serum free-T₄ levels, which should be maintained in the upper half of the normal range in these patients.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine. The synthetic T₄ in LEVOTHROID® is identical to that produced naturally by the human thyroid gland. Although there has been a reported association between prolonged thyroid hormone therapy and breast cancer, this has not been confirmed. Patients receiving LEVOTHROID® for appropriate clinical indications should be titrated to the lowest effective replacement dose.

Pregnancy

Category A

Studies in women taking levothyroxine sodium during pregnancy have not shown an increased risk of congenital abnormal-ities. Therefore, the possibility of fetal harm appears remote. LEVOTHROID® should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, pre-eclampsia, stillbirth and premature delivery. Maternal hypothyroidism may have an adverse effect on fetal and childhood growth and development. During pregnancy, serum T₄ levels may decrease and serum TSH levels increase to values outside the normal range. Since elevations in serum TSH may occur as early as 4 weeks gestation, pregnant women taking LEVOTHROID® should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of LEVOTHROID® . Since postpartum TSH levels are similar to preconception values, the LEVOTHROID® dosage should return to the pre-pregnancy dose immediately after delivery. A serum TSH level should be obtained 6-8 weeks postpartum.

Thyroid hormones cross the placental barrier to some extent as evidenced by levels in cord blood of athyreotic fetuses being approximately one-third maternal levels. Transfer of thyroid hormone from the mother to the fetus, however, may not be adequate to prevent in utero hypothyroidism.

Nursing Mothers

Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when LEVOTHROID® is administered to a nursing woman. However, adequate replacement doses of levothyroxine are generally needed to maintain normal lactation.

Pediatric Use

General

The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development. The initial dose of levothyroxine varies with age and body weight (see DOSAGE AND ADMINISTRATION, Table 3). Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters (see PRECAUTIONS, Laboratory Tests).

In children in whom a diagnosis of permanent hypothyroidism has not been established, it is recommended that levothyroxine administration be discontinued for a 30-day trial period, but only after the child is at least 3 years of age. Serum T₄ and TSH levels should then be obtained. If the T₄ is low and the TSH high, the diagnosis of permanent hypothyroidism is established, and levothyroxine therapy should be reinstituted. If the T₄ and TSH levels are normal, euthyroidism may be assumed and, therefore, the hypothyroidism can be considered to have been transient. In this instance, however, the physician should carefully monitor the child and repeat the thyroid function tests if any signs or symptoms of hypothyroidism develop. In this setting, the clinician should have a high index of suspicion of relapse. If the results of the levothyroxine withdrawal test are inconclusive, careful follow-up and subsequent testing will be necessary.

Since some more severely affected children may become clinically hypothyroid when treatment is discontinued for 30 days, an alternate approach is to reduce the replacement dose of levothyroxine by half during the 30-day trial period. If, after 30 days, the serum TSH is elevated above 20 mU/L, the diagnosis of permanent hypothyroidism is confirmed, and full replacement therapy should be resumed. However, if the serum TSH has not risen to greater than 20 mU/L, levothyroxine treatment should be discontinued for another 30-day trial period followed by repeat serum T₄ and TSH testing.

The presence of concomitant medical conditions should be considered in certain clinical circumstances and, if present, appropriately treated (see PRECAUTIONS).

Congenital Hypothyroidism

(see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION)

Rapid restoration of normal serum T₄ concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, LEVOTHROID® therapy should be initiated immediately upon diagnosis and is generally continued for life.

During the first 2 weeks of LEVOTHROID® therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration from avid suckling.

The patient should be monitored closely to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment has been associated with craniosynostosis in infants, and may adversely affect the tempo of brain maturation and accelerate the bone age with resultant premature closure of the epiphyses and compromised adult stature.

Acquired Hypothyroidism in Pediatric Patients

The patient should be monitored closely 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 epiphy-seal 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.

Geriatric Use

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).

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 18 mg of levothy-roxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

Treatment of Overdosage

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

Acute Massive Overdosage

This may be a life-threatening emergency, therefore, symptomatic and supportive therapy should be instituted immediately. If not contraindicated (e. g. , by seizures, coma, or loss of the gag reflex), the stomach should be emptied by emesis or gastric lavage to decrease gastrointestinal absorption. Activated charcoal or cholestyramine may also be used to decrease absorption. Central and peripheral increased sympathetic activity may be treated by administering β-receptor antagonists, e. g. , propranolol, provided there are no medical contraindications to their use. Provide respiratory support as needed;control congestive heart failure and arrhythmia;control fever, hypoglycemia, and fluid loss as necessary. Large doses of antithyroid drugs (e. g. , methimazole or propylthiouracil) followed in one to two hours by large doses of iodine may be given to inhibit synthesis and release of thyroid hormones. Glucocorticoids may be given to inhibit the conversion of T₄ to T₃. Plasmapheresis, charcoal hemoperfusion and exchange transfusion have been reserved for cases in which continued clinical deterioration occurs despite conventional therapy. Because T₄ is highly protein bound, very little drug will be removed by dialysis.

Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T₃ and T₄ levels) or overt thyrotoxico-sis 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). LEVOTHROID® is contraindicated in patients with hypersensitivity to any of the inactive ingredients in LEVOTHROID® tablets (see DESCRIPTION, Inactive Ingredients).

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 deio-dination 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).

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 LEVOTHROID® tablets, compared to an equal nominal dose of oral levothy-roxine sodium solution, is approximately 94%. 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 eighty-percent 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 deiodi-nated 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

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

1. 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.
2. 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 LEVOTHROID® . If you have diabetes, monitor your blood and/or urinary glucose levels as directed by your physician and immediately report any changes to your physi-cian. If you are taking anticoagulants (blood thinners), your clotting status should be checked frequently.
3. Use LEVOTHROID® 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.
4. The levothyroxine in LEVOTHROID® 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).
5. Take LEVOTHROID® as a single dose, preferably on an empty stomach, one-half to one hour before breakfast. Levothyroxine absorption is increased on an empty stomach.
6. It may take several weeks before you notice an improvement in your symptoms.
7. 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.
8. Notify your physician if you become pregnant while taking LEVOTHROID® . It is likely that your dose of LEVOTHROID® will need to be increased while you are pregnant.
9. Notify your physician or dentist that you are taking LEVOTHROID® prior to any surgery.
10. Partial hair loss may occur rarely during the first few months of LEVOTHROID® therapy, but this is usually temporary.
11. LEVOTHROID® should not be used as a primary or adjunctive therapy in a weight control program.
12. Keep LEVOTHROID® out of the reach of children. Store LEVOTHROID® away from heat, moisture, and light.
13. Agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine sodium tablets. Therefore, levothyroxine sodium tablets should not be administered within 4 hrs of these agents.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

LEVOTHYROXINE - ORAL

(lee-voe-thye-ROX-een)

COMMON BRAND NAME(S): Levothroid, Levoxyl, Synthroid, Unithroid

WARNING: This medication should not be used either alone or in combination with diet pills to treat obesity or for weight loss because serious, even life-threatening, effects could occur. Large doses of this medication, especially with diet pills, may cause symptoms of toxicity. See the Side Effects and Overdose sections for more information.

USES: Levothyroxine is used to treat an underactive thyroid (hypothyroidism). It replaces the hormone that is normally produced by the thyroid gland. Low thyroid levels can occur naturally or when the thyroid gland is injured by radiation/medications or removed by surgery. It is important to have adequate levels of thyroid hormone in your bloodstream to maintain normal mental and physical activity. In children, adequate levels of thyroid hormone are important for normal mental and physical growth and development.

This medication is used to treat other types of thyroid disorders as well (e.g., certain types of goiters, thyroid nodules, thyroiditis, thyroid cancer).

HOW TO USE: Take this medication by mouth usually once a day on an empty stomach, 1/2 to 1 hour before breakfast, or as directed by your doctor. To prevent difficulty swallowing the tablet, take it with a full glass of water unless otherwise directed by your doctor.

For children who cannot swallow whole tablets, crush the tablet and mix in 1 or 2 teaspoons (5 or 10 milliliters) of water, and give using a spoon or dropper as soon as possible after preparation. Do not store the mixture for later use. Do not mix crushed tablets in soybean infant formula. Consult your pharmacist for more information.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day. Your doctor may need to adjust your dosage based on your medical condition, your response to therapy, and your laboratory test results.

Do not stop taking this medication without consulting with your doctor. Replacement therapy is usually taken for life.

It may take up to 4-6 weeks before the full benefits of this medication take effect. Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Symptoms of low thyroid levels include fatigue, muscle aches, constipation, dry skin, weight gain, slow heart rate, sensitivity to cold, or dry brittle hair that tends to fall out easily. These symptoms should disappear as your body adjusts to the medication. If they persist or become bothersome, notify your doctor promptly.

Headache, nervousness, trembling, sweating, increased appetite, diarrhea, weight loss or insomnia may occur. If any of these effects persist or worsen, notify your doctor promptly.

In rare instances, some hair loss may occur during the first few months of starting this drug. This effect is usually temporary as your body adjusts to this medication. If this effect persists or worsens, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Seek immediate medical attention if you have any of these very unlikely but serious side effects: chest pain, rapid or irregular heartbeat, shortness of breath, seizures.

An allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of an allergic reaction include: rash, itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking levothyroxine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: overactive thyroid conditions (e.g., thyrotoxicosis), a heart attack (acute myocardial infarction), adrenal gland problems (e.g., uncorrected adrenal insufficiency).

Do not use thyroid drugs for weight control.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart problems (e.g., hypertension, congestive heart failure, arrhythmias, coronary artery disease), diabetes, male or female infertility problems (unless caused by underactive thyroid disease), bone loss disease (e.g., osteoporosis), other hormone disorders (e.g., hypothalamic/pituitary hormone deficiencies, autoimmune polyglandular syndrome), certain thyroid problems (e.g., nontoxic diffuse goiter, nodular thyroid disease), blood clotting disorders.

Notify your doctor or dentist that you are taking this medication prior to any surgery.

Caution is advised when using this drug in children because overuse may reduce the child's future adult height. Consult your doctor for details.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug.

Current information shows that this drug may be used during pregnancy. Tell your doctor if you are pregnant because your dose will have to be adjusted.

Small amounts of this drug pass into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription drugs you may use, especially of: warfarin, digoxin, estrogen products (including estrogen-containing birth control pills), diabetes medicines (e.g., insulin, glipizide, rosiglitazone), amiodarone, iodide (including radiographic contrast agents containing iodine), lithium, anti-thyroid agents (e.g., methimazole, propylthiouracil), androgens/anabolic steroids, glucocorticoids (e.g., dexamethasone, prednisone), high dose salicylates (e.g., aspirin), phenobarbital, rifamycins (e.g., rifampin), beta blockers (e.g., propranolol), antidepressants (e.g., amitriptyline, maprotiline, sertraline), cytokines (e.g., interferon-alpha, interleukin-2), growth hormones, ketamine, theophylline.

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids) because they may contain ingredients such as decongestants or caffeine that could increase your heart rate or blood pressure. Ask your pharmacist about the safe use of these products.

Certain medicines may decrease absorption of this drug into your bloodstream. Therefore, take levothyroxine 4 hours apart from: calcium supplements, iron supplements, antacids, simethicone, cholestyramine, colesevelam, colestipol, sucralfate, sodium polystyrene sulfonate.

Certain foods may decrease absorption of this medication when taken at the same time. Take levothyroxine separately from: soybean flour (soybean infant formula), walnuts, dietary fiber.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: excessive sweating, extreme nervousness, fast/irregular heartbeat, chest pain, seizures.

NOTES: Laboratory and/or medical tests (e.g., thyroid function tests) should be done periodically to monitor the effectiveness of this medication. Inform your doctor if you change to a different brand of thyroid hormone.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. Call your doctor if you miss 2 or more doses in a row.

STORAGE: Store at room temperature (77 degrees F or 25 degrees C) away from light and moisture. Brief storage between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.