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SYNTHROID® Knoll Levothyroxine Sodium Thyroid Hormone
 
Action and Clinical

The synthesis and secretion of the major thyroid hormones, L-thyroxine (T 4) and L-triiodothyronine (T 3), from the normally functioning thyroid gland are regulated by complex feedback mechanisms of the hypothalamic-pituitary-thyroid axis. The thyroid gland is stimulated to secrete thyroid hormones by the action of thyrotropin (thyroid stimulating hormone, TSH), which is produced in the anterior pituitary gland. TSH secretion is in turn controlled by thyrotropin-releasing hormone (TRH) produced in the hypothalamus, circulating thyroid hormones, and possibly other mechanisms. Thyroid hormones circulating in the blood act as feedback inhibitors of both TSH and TRH secretion. Thus, when serum concentrations of T 3 and T 4 are increased, secretion of TSH and TRH decreases. Conversely, when serum thyroid hormone concentrations are decreased, secretion of TSH and TRH is increased. Administration of exogenous thyroid hormones to euthyroid individuals results in suppression of endogenous thyroid hormone secretion.:

The mechanisms by which thyroid hormones exert their physiologic actions have not been completely elucidated. T 4 and T 3 are transported into cells by passive and active mechanisms. T 3 in cell cytoplasm and T 3 generated from T 4 within the cell diffuse into the nucleus and bind to thyroid receptor proteins, which appear to be primarily attached to DNA. Receptor binding leads to activation or repression of DNA transcription, thereby altering the amounts of mRNA and resultant proteins. Changes in protein concentrations are responsible for the metabolic changes observed in organs and tissues.

Thyroid hormones enhance oxygen consumption of most body tissues and increase the basal metabolic rate and metabolism of carbohydrates, lipids, and proteins. Thus, they exert a profound influence on every organ system and are of particular importance in the development of the CNS. Thyroid hormones also appear to have direct effects on tissues, such as increased myocardial contractility and decreased systemic vascular resistance.

The physiologic effects of thyroid hormones are produced primarily by T 3, a large portion of which is derived from the deiodination of T 4 in peripheral tissues. About 70 to 90% of peripheral T 3 is produced by monodeiodination of T 4 at the 5nbsp;position (outer ring). Peripheral monodeiodination of T 4 at the 5 position (inner ring) results in the formation of reverse triiodothyronine (rT 3), which is calorigenically inactive.

Pharmacokinetics: Few clinical studies have evaluated the kinetics of orally administered thyroid hormone. In animals, the most active sites of absorption appear to be the proximal and mid-jejunum. T 4 is not absorbed from the stomach and little, if any, drug is absorbed from the duodenum. There seems to be no absorption of T 4 from the distal colon in animals. A number of human studies have confirmed the importance of an intact jejunum and ileum for T 4 absorption and have shown some absorption from the duodenum. Studies involving radioiodinated T 4 fecal tracer excretion methods, equilibration, and AUC methods have shown that absorption varies from 48 to 80% of the administered dose. The extent of absorption is increased in the fasting state and decreased in malabsorption syndromes, such as sprue. Absorption may also decrease with age. The degree of T 4 absorption is dependent on the product formulation as well as on the character of the intestinal contents, the intestinal flora, including plasma protein and soluble dietary factors, which bind thyroid hormone, making it unavailable for diffusion. Decreased absorption may result from administration of infant soybean formula, ferrous sulfate, sodium polystyrene sulfonate, aluminum hydroxide, sucralfate, or bile acid sequestrants. T 4 absorption following i.m. administration is variable.

Distribution of thyroid hormones in human body tissues and fluids has not been fully elucidated. More than 99% of circulating hormones is bound to serum proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA). T 4 is more extensively and firmly bound to serum proteins than is T 3. Only unbound thyroid hormone is metabolically active. The higher affinity of TBG and TBPA for T 4 partly explains the higher serum levels, slower metabolic clearance, and longer serum elimination half-life of this hormone.

Certain drugs and physiologic conditions can alter the binding of thyroid hormones to serum proteins and/or the concentrations of the serum proteins available for thyroid hormone binding. These effects must be considered when interpreting the results of thyroid function tests (see Precautions, Drug Interactions and Laboratory Test Interactions).

T 4 is eliminated slowly from the body, with a half-life of 6 to 7 days. T 3 has a half-life of 1 to 2 days. The liver is the major site of degradation for both hormones. T 4 and T 3 are conjugated with glucuronic and sulfuric acids and excreted in the bile. There is an enterohepatic circulation of thyroid hormones, as they are liberated by hydrolysis in the intestine and reabsorbed. A portion of the conjugated material reaches the colon unchanged, is hydrolyzed there, and is eliminated as free compounds in the feces. In man, approximately 20 to 40% of T 4 is eliminated in the stool. About 70% of the T 4 secreted daily is deiodinated to yield equal amounts of T 3 and rT 3. Subsequent deiodination of T 3 and rT 3 yields multiple forms of diiodothyronine. A number of other minor T 4 metabolites have also been identified. Although some of these metabolites have biologic activity, their overall contribution to the therapeutic effect of T 4 is minimal.

Indications And Clinical Uses :

As replacement or supplemental therapy in patients of any age or state (including pregnancy) with hypothyroidism of any etiology except transient hypothyroidism during the recovery phase of subacute thyroiditis; primary hypothyroidism resulting from thyroid dysfunction, primary atrophy, or partial or total absence of the thyroid gland, or from the effects of surgery, radiation or drugs, with or without the presence of goiter, including subclinical hypothyroidism; secondary (pituitary) hypothyroidism; and tertiary (hypothalamic) hypothyroidism (see Contraindications and Precautions). Levothyroxine injection can be used i.v. when rapid repletion is required, and either i.v. or i.m. when the oral route is precluded.

As a pituitary TSH suppressant in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto's), multinodular goiter, and in conjunction with surgery and radioactive iodine therapy in the management of thyrotropin-dependent well-differentiated papillary or follicular carcinoma of the thyroid.

Contra-Indications:

In patients with untreated thyrotoxicosis of any etiology, acute myocardial infarction, or an apparent hypersensitivity to thyroid hormones or any of the inactive product constituents. (Note: The 50 µg tablet is formulated without color additives for patients who are sensitive to dyes.) There is no well-documented evidence of true allergic or idiosyncratic reactions to thyroid hormone. Levothyroxine is also contraindicated in patients with uncorrected adrenal insufficiency, as thyroid hormones increase tissue demands for adrenocortical hormones and may thereby precipitate acute adrenal crisis (see Precautions).WarningWarnings

Warnings in Clinical States:

Thyroid hormones, either alone or together with other therapeutic agents, should not be used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

The use of levothyroxine in the treatment of obesity, either alone or in combination with other drugs, is unjustified. The use of levothyroxine is also unjustified in the treatment of male or female infertility unless this condition is associated with hypothyroidism.

Precautions:

General: Levothyroxine should be used with caution in patients with cardiovascular disorders, including angina, coronary artery disease, and hypertension, and in the elderly who have a greater likelihood of occult cardiac disease. Concomitant administration of thyroid hormone and sympathomimetic agents to patients with coronary artery disease may increase the risk of coronary insufficiency.

Use of levothyroxine in patients with concomitant diabetes mellitus, diabetes insipidus or adrenal cortical insufficiency may aggravate the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases may therefore be required. Treatment of myxedema coma may require simultaneous administration of glucocorticoids (see Dosage).

T 4 enhances the response to anticoagulant therapy. Prothrombin time should be closely monitored in patients taking both levothyroxine and oral anticoagulants, and the dosage of anticoagulant adjusted accordingly.

The bioavailability of levothyroxine may differ to some extent among marketed brands. Once the patient is stabilized on a particular brand of levothyroxine sodium, caution should be exercised when a change in drug product brand is implemented.

It has been shown that differences in formulations of levothyroxine, despite an identical content of active ingredient, may be associated with differences in fractional gastrointestinal absorption. These differences may not be observed through measurement of total T 3 and T 4 serum levels. It is therefore, recommended that patients who are switched from one levothyroxine formulation to another be retitrated to the desired thyroid function. Accuracy in retitration can best be achieved by using sensitive thyrotropin assays.

The intestinal absorption of levothyroxine may be impaired in patients with absorption disorder; in such patients, higher dosage levels of levothyroxine may be required.

Seizures have been reported rarely in association with the initiation of levothyroxine therapy, and may be related to the effect of thyroid hormone on seizure threshold.

Lithium blocks the TSH-mediated release of T 4 and T 3. Thyroid function should therefore be carefully monitored during lithium initiation, stabilization, and maintenance. If hypothyroidism occurs during lithium treatment, a higher than usual levothyroxine dose may be required.

Laboratory Tests: Treatment of patients with levothyroxine requires periodic assessment of thyroid status by appropriate laboratory tests and clinical evaluation. Selection of appropriate tests for the diagnosis and management of thyroid disorders depends on patient variables such as presenting signs and symptoms, pregnancy, and concomitant medications. A combination of sensitive TSH assay and free T 4 estimate (free T 4 index, FT 4I) are recommended to confirm a diagnosis of thyroid disease. Normal ranges for these parameters are age-specific in newborns and younger children.

TSH alone or initially may be useful for thyroid disease screening and for monitoring therapy for primary hypothyroidism as a linear inverse correlation exists between serum TSH and free T 4. Measurement of total serum T 4 and T 3, resin T 3 uptake, and free T 3 concentrations may also be useful. Antithyroid microsomal antibodies are an indicator of autoimmune thyroid disease. Positive microsomal antibody presence in an euthyroid patient is a major risk factor for the development of hypothyroidism. An elevated serum TSH in the presence of a normal T 4 may indicate subclinical hypothyroidism. Intracellular resistance to thyroid hormone is quite rare, and is suggested by clinical signs and symptoms of hypothyroidism in the presence of high serum T 4 levels. Adequacy of levothyroxine therapy for hypothyroidism of pituitary or hypothalamic origin should be assessed by measuring FT 4I, which should be maintained in the upper half of the normal range. Measurement of TSH is not a reliable indicator of response to therapy for this condition. Adequacy of levothyroxine therapy for congenital and acquired pediatric hypothyroidism should be assessed by measuring serum total T 4 or free T 4; these should be maintained in the upper half of the normal range. In congenital hypothyroidism, serum TSH normalization may lag behind serum T 4 normalization by 2 to 3 months or longer. In rare patients, serum TSH remains relatively elevated despite clinical euthyroidism and age-specific normal T 4 or free T 4 levels (see Children).

Drug Interactions :

The magnitude and relative clinical importance of the effects noted below are likely to be patient-specific and may vary by such factors as age, gender, race, intercurrent illnesses, dose of either agents, additional concomitant medications, and timing of drug administration. Any agent that alters thyroid hormone synthesis, secretion, distribution, effect on target tissues, metabolism, or elimination may alter the optimal therapeutic dose of levothyroxine.

Levothyroxine Absorption: The following agents may bind and decrease absorption of levothyroxine from the gastrointestinal tract: aluminum hydroxide, cholestyramine resin, colestipol HCl, ferrous sulfate, sodium polystyrene sulfonate, soybean flour (e.g., infant formula), sucralfate.

Binding to Serum Proteins: The following agents may either inhibit levothyroxine binding to serum proteins or alter the concentrations of serum binding proteins: androgens and related anabolic hormones, asparaginase, clofibrate, estrogens and estrogen-containing compounds, 5-fluorouracil, furosemide, glucocorticoids, meclofenamic acid, mefenamic acid, methadone, perphenazine, phenylbutazone, phenytoin, salicylates, tamoxifen.

Thyroid Physiology: The following agents may alter thyroid hormone or TSH levels, generally by effects on thyroid hormone synthesis, secretion, distribution, metabolism, hormone action, or elimination, or altered TSH secretion: aminoglutethimide, p-aminosalicylic acid, amiodarone, androgens and related anabolic hormones, complex anions (thiocyanate, perchlorate, pertechnetate), antithyroid drugs, b-adrenergic blocking agents, carbamazepine, chloral hydrate, diazepam, dopamine and dopamine agonists, ethionamide, glucocorticoids, heparin, hepatic enzyme inducers, insulin, iodinated cholestographic agents, iodine-containing compounds, levodopa, lovastatin, lithium, 6-mercaptopurine, metoclopramide, mitotane, nitroprusside, phenobarbital, phenytoin, resorcinol, rifampin, somatostatin analogs, sulfonamides, sulfonylureas, thiazide diuretics.

Adrenocorticoids: Metabolic clearance of adrenocorticoids is decreased in hypothyroid patients and increased in hyperthyroid patients, and may therefore change with changing thyroid status.

Amiodarone: Amiodarone therapy alone can cause hypothyroidism or hyperthyroidism.

Anticoagulants (oral): The hypoprothrombinemic effect of anticoagulants may be potentiated, apparently by increased catabolism of vitamin K-dependent clotting factors.

Antidiabetic agents (insulin, sulfonylureas): Requirements for insulin or oral antidiabetic agents may be reduced in hypothyroid patients with diabetes mellitus, and may subsequently increase with the initiation of thyroid hormone replacement therapy.

b-adrenergic Blocking Agents: Actions of some beta-blocking agents may be impaired when hypothyroid patients become euthyroid.

Cytokines (interferon, interleukin): Cytokines have been reported to induce both hyperthyroidism and hypothyroidism.

Digitalis Glycosides: Therapeutic effects of digitalis glycosides may be reduced. Serum digitalis levels may be decreased in hyperthyroidism or when a hypothyroid patient becomes euthyroid.

Ketamine: Marked hypertension and tachycardia have been reported in association with concomitant administration of levothyroxine and ketamine.

Maprotiline: Risk of cardiac arrhythmias may increase.

Sodium iodide (

Somatrem/Somatropin: Excessive concurrent use of thyroid hormone may accelerate epiphyseal closure. Untreated hypothyroidism may interfere with the growth response to somatrem or somatropin.

Theophylline: Theophylline clearance may decrease in hypothyroid patients and returns toward normal when the euthyroid state is achieved.

Tricyclic Antidepressants: Concurrent use may increase the therapeutic and toxic effects of both drugs, possibly due to increased catecholamine sensitivity. Onset of action of tricyclics may be accelerated.

Sympathomimetic Agents: Possible increased risk of coronary insufficiency in patients with coronary artery disease.

Laboratory Test Interactions : A number of drugs or moieties are known to alter serum levels of TSH, T 4 and T 3 and may thereby influence the interpretation of laboratory tests of thyroid function (see Drug Interactions).

Changes in TBG concentration should be taken into consideration when interpreting T 4 and T 3 values. Drugs such as estrogens and estrogen-containing oral contraceptives increase serum TBG concentrations. TBG concentrations may also be increased during pregnancy and in 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 is approximately 1 in 9 000. Certain drugs such as salicylates inhibit the protein-binding of T 4. In such cases, the unbound (free) hormone should be measured. Alternatively, an indirect measure of free thyroxine, such as the FT 4I, may be used.

Medicinal or dietary iodine interferes with in vivo tests of radioiodine uptake, producing low uptakes which may not indicate a true decrease in hormone synthesis.

Persistent clinical and laboratory evidence of hypothyroidism despite an adequate replacement dose suggests either poor patient compliance, impaired absorption, drug interactions, or decreased potency of the preparation due to improper storage.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Although animal studies to determine the mutagenic or carcinogenic potential of thyroid hormones have not been performed, synthetic T 4 is identical to that produced by the human thyroid gland. A reported association between prolonged thyroid hormone therapy and breast cancer has not been confirmed and patients receiving levothyroxine for established indications should not discontinue therapy.

Pregnancy: Studies in pregnant women have not shown that levothyroxine increases the risk of fetal abnormalities if administered during pregnancy. If levothyroxine is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, levothyroxine should be used during pregnancy only if clearly needed.

Thyroid hormones cross the placental barrier to some extent. T 4 levels in the cord blood of athyroid fetuses have been shown to be about one-third of maternal levels. Nevertheless, maternal-fetal transfer of T 4 may not prevent in utero hypothyroidism.

Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion and pre-eclampsia, and has been reported to have an adverse effect on fetal and childhood development. On the basis of current knowledge, levothyroxine should therefore not be discontinued during pregnancy, and hypothyroidism diagnosed during pregnancy should be treated. Studies have shown that during pregnancy T 4 concentrations may decrease and TSH concentrations may increase to values outside normal ranges. Postpartum values are similar to preconception values. Elevations in TSH may occur as early as 4 weeks gestation.

Pregnant women who are maintained on levothyroxine should have their TSH measured periodically. An elevated TSH should be corrected by an increase in levothyroxine dose. After pregnancy, the dose can be decreased to the optimal preconception dose.

Lactation: Minimal amounts of thyroid hormones are excreted in human milk. Thyroid hormones are not associated with serious adverse reactions and do not have known tumorigenic potential. While caution should be exercised when levothyroxine is administered to a nursing woman, adequate replacement doses of levothyroxine are generally needed to maintain normal lactation.

Children: Congenital hypothyroidism: Rapid restoration of normal serum T 4 concentrations is essential to prevent deleterious neonatal thyroid hormone deficiency effects on intelligence, overall growth, and development. Treatment should be initiated immediately upon diagnosis and generally maintained for life. The therapeutic goal is to maintain serum total T 4 or FT 4 in the upper half of the normal range and serum TSH in the normal range.

An initial starting dose of 10 to 15 µg/kg/day (ages 0 to 3 months) will generally increase serum T 4 concentrations to the upper half of the normal range in less than 3 weeks. Clinical assessment of growth, development, and thyroid status should be monitored frequently. In most cases, the levothyroxine dose per body weight will decrease as the patient grows through infancy and childhood (see Dosage, Children, Table I). Prolonged use of large doses in infants may be associated with temperament problems, which appear to be transient.

Thyroid function tests (serum total T 4 or FT 4, and TSH) should be monitored closely and used to determine the adequacy of levothyroxine therapy. Serum T 4 normalization is usually followed by a rapid decline in TSH. Nevertheless, TSH normalization may lag behind T 4 normalization by 2 to 3 months or longer. The relative serum TSH elevation is more marked in the early months, but can persist to some degree throughout life. In rare patients TSH remains relatively elevated despite clinical euthyroidism and age-specific normal total T 4 or FT 4 levels. Increasing the levothyroxine dosage to suppress TSH into the normal range may produce overtreatment, with an elevated serum T 4 and clinical features of hyperthyroidism including: irritability, increased appetite with diarrhea, and sleeplessness. Another risk of prolonged overtreatment in infants is premature cranial synostosis.

Hypothyroidism permanence may be assessed when transient hypothyroidism is suspected. Levothyroxine therapy may be interrupted for 30 days after 3 years of age and serum T 4 and TSH measured. Low T 4 and elevated TSH confirms permanent hypothyroidism; therapy should be re-instituted. If T 4 and TSH remain in the normal range, a presumptive diagnosis of transient hypothyroidism can be made. In this instance, continued clinical monitoring and periodic thyroid function test reevaluation may be warranted.

Acquired hypothyroidism: The initial levothyroxine dose varies with age and body weight, and should be adjusted to maintain serum total T 4 or free T 4 levels in the upper half of the normal range. In general, unless there are overriding clinical concerns, children should be started on a full replacement dose. Children with underlying heart disease should be started at lower dosages, with careful upward titration. Children with severe, longstanding hypothyroidism may also be started on a lower initial dose followed by an upward titration, attempting to avoid premature epiphyseal closure. The recommended dose per body weight decreases with age (see Dosage, Children, Table I).

Treated children may resume growth at a greater than normal rate (period of transient catch-up growth). In some cases the catch-up may be adequate to normalize growth. However, severe and prolonged hypothyroidism may reduce adult height. Excessive thyroxine replacement may initiate accelerated bone maturation, producing disproportionate skeletal age advancement and shortened adult stature.

Hypothyroidism permanence may be assessed when transient hypothyroidism is suspected. Levothyroxine therapy may be interrupted for 30 days and serum T 4 and TSH measured. Low T 4 and elevated TSH confirms permanent hypothyroidism; therapy should be re-instituted. If T 4 and TSH remain in the normal range, a presumptive diagnosis of transient hypothyroidism can be made. In this instance, continued clinical monitoring and periodic thyroid function test reevaluation may be warranted.

Adverse Reactions:

:Adverse reactions other than those indicative of thyrotoxicosis as a result of therapeutic overdosage, either initially or during the maintenance periods, are rare (see Overdose: Symptoms and Treatment). Craniosynostosis has been associated with iatrogenic hyperthyroidism in infants receiving thyroid hormone replacement therapy. Inadequate doses of levothyroxine sodium may produce or fail to resolve symptoms of hypothyroidism. Hypersensitivity reactions to the product excipients, such as rash and urticaria, may occur. Partial hair loss may occur during the initial months of therapy, but is generally transient. The incidence of continued hair loss is unknown. Pseudotumor cerebri has been reported in pediatric patients receiving thyroid hormone replacement therapy.

Symptoms And Treatment Of Overdose :

Symptoms: Excessive doses of levothyroxine result in a hypermetabolic state indistinguishable from thyrotoxicosis of endogenous origin. Signs and symptoms of thyrotoxicosis include exophthalmic goiter, weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, angina pectoris, tremors, insomnia, heat intolerance, fever, and menstrual irregularities. Symptoms are not always evident or may not appear until several days after ingestion.

Treatment: Levothyroxine should be reduced in dose or temporarily discontinued if signs and symptoms of overdosage appear.

In the treatment of acute massive levothyroxine overdosage, symptomatic and supportive therapy should be instituted immediately. Treatment is aimed at reducing gastrointestinal absorption and counteracting central and peripheral effects, mainly those of increased sympathetic activity. The stomach should be emptied immediately by emesis or gastric lavage if not otherwise contraindicated (e.g., by coma, convulsions or loss of gag reflex). Cholestyramine and activated charcoal have also been used to decrease levothyroxine absorption. Oxygen should be administered and ventilation maintained as necessary. b-receptor antagonists, particularly propranolol, are useful in counteracting many of the effects of increased sympathetic activity. Propranolol may be administered i.v. at a dosage of 1 to 3 mg over a 10 minute period or orally, 80 to 160 mg/day, especially when no contraindications exist for its use. Cardiac glycosides may be administered if congestive heart failure develops. Measures to control fever, hypoglycemia, or fluid loss should be initiated as necessary. Glucocorticoids may be administered to inhibit the conversion of T 4 to T 3.

Since T 4 is extensively protein bound, very little drug will be removed by dialysis.

Dosage And Administration:

The dosage and rate of administration of levothyroxine is determined by the indication, and must in every case be individualized according to patient response and laboratory findings.

Adults: Hypothyroidism: The goal of therapy for primary hypothyroidism is to achieve and maintain a clinical and biochemical euthyroid state with consequent resolution of hypothyroid signs and symptoms. The starting dose of levothyroxine, the frequency of dose titration, and the optimal full replacement dose must be individualized for every patient, and will be influenced by such factors as age, weight, cardiovascular status, presence of other illness, and the severity and duration of hypothyroid symptoms.

The usual full replacement dose of levothyroxine for younger, healthy adults is approximately 1.6 µg/kg/day administered once daily. In the elderly, the full replacement dose may be altered by decreases in T 4 metabolism and levothyroxine sodium absorption. Older patients may require less than 1 µg/kg/day. Children generally require higher doses (see Children). Women who are maintained on levothyroxine during pregnancy may require increased doses (see Precautions, Pregnancy).

Therapy is usually initiated in younger, healthy adults at the anticipated full replacement dose. Clinical and laboratory evaluations should be performed at 6 to 8 week intervals (2 to 3 weeks in severely hypothyroid patients), and the dosage adjusted by 12.5 to 25 µg increments until the serum TSH concentration is normalized and signs and symptoms resolve. In older patients or in younger patients with a history of cardiovascular disease, the starting dose should be 12.5 to 50 µg once daily with adjustments of 12.5 to 25 µg every 3 to 6 weeks until TSH is normalized. If cardiac symptoms develop or worsen, the cardiac disease should be evaluated and the dose of levothyroxine reduced. Rarely, worsening angina or other signs of cardiac ischemia may prevent achieving a TSH in the normal range.

Treatment of subclinical hypothyroidism may require lower than usual replacement doses, e.g., 1 µg/kg/day. Patients for whom treatment is not initiated should be monitored yearly for changes in clinical status, TSH, and thyroid antibodies.

In patients with hypothyroidism resulting from pituitary or hypothalamic disease, the possibility of secondary adrenal insufficiency should be considered, and if present, treated with glucocorticoids prior to initiation of levothyroxine. The adequacy of levothyroxine therapy should be assessed in these patients by measuring FT 4I, which should be maintained in the upper half of the normal range, in addition to clinical assessment. Measurement of TSH is not a reliable indicator of response to therapy for this condition.

Few patients require doses greater than 200 µg/day. An inadequate response to daily doses of 300 to 400 µg/day is rare, and may suggest malabsorption, poor patient compliance, and/or drug interactions.

Once optimal replacement is achieved, clinical and laboratory evaluations should be conducted at least annually or whenever warranted by a change in patient status. Levothyroxine products from different manufacturers should not be used interchangeably unless retesting of the patient and retitration of the dosage, as necessary, accompanies the product switch.

Levothyroxine injection by the i.v. or i.m. route can be substituted for the oral dosage form when rapid repletion is required or oral administration is precluded. The initial parenteral dosage should be approximately one-half the previously established oral dosage of levothyroxine tablets. Close observation of the patient is recommended, with adjustment of the dosage as needed. Administration of levothyroxine injection by the s.c. route is not recommended as studies have shown that the influx of T 4 from the s.c. site is very slow, and depends on many factors such as volume of injection, the anatomic site of injection, ambient temperature, and presence of venospasm.

Myxedema Coma: Myxedema coma represents the extreme expression of severe hypothyroidism and is considered a medical emergency. It is characterized by hypothermia, hypotension, hypoventilation, hyponatremia, and bradycardia. In addition to restoration of normal thyroid hormone levels, therapy should be directed at the correction of electrolyte disturbances and possible infection. Because the mortality rate of patients with untreated myxedema coma is high, treatment must be started immediately, and should include appropriate supportive therapy and corticosteroids to prevent adrenal insufficiency. Possible precipitating factors should also be identified and treated. Levothyroxine may be given via nasogastric tube, but the preferred route of administration is i.v. A bolus dose of levothyroxine is given immediately to replete the peripheral pool of T 4, usually 300 to 500 µg. Although such a dose is usually well-tolerated even in the elderly, the rapid i.v. administration of large doses of levothyroxine to patients with cardiovascular disease is clearly not without risks. Under such circumstances, i.v. therapy should not be undertaken without weighing the alternate risks of myxedema coma and the cardiovascular disease. Clinical judgment in this situation may dictate smaller i.v. doses of levothyroxine. The initial dose is followed by daily i.v. doses of 75 to 100 µg until the patient is stable and oral administration is feasible. Normal T 4 levels are usually achieved in 24 hours, followed by progressive increases in T 3. Improvement in cardiac output, blood pressure, temperature, and mental status generally occur within 24 hours, with improvement in many manifestations of hypothyroidism in 4 to 7 days.

TSH Suppression in Thyroid Cancer and Thyroid Nodules: The rationale for TSH suppression therapy is that a reduction in TSH secretion may decrease the growth and function of abnormal thyroid tissue. Exogenous thyroid hormone may inhibit recurrence of tumor growth and may produce regression of metastases from well-differentiated (follicular and papillary) carcinoma of the thyroid. It is used as ancillary therapy of these conditions following surgery or radioactive iodine therapy. Medullary and anaplastic carcinoma of the thyroid is unresponsive to TSH suppression therapy. TSH suppression is also used in treating nontoxic solitary nodules and multinodular goiters.

No controlled studies have compared the various degrees of TSH suppression in the treatment of either benign or malignant thyroid nodular disease. Further, the effectiveness of TSH suppression for benign nodular disease is controversial. The dose of levothyroxine used for TSH suppression should therefore be individualized by the nature of the disease, the patient being treated, and the desired clinical response, weighing the potential benefits of therapy against the risks of iatrogenic thyrotoxicosis. In general, levothyroxine should be given in the smallest dose that will achieve the desired clinical response.

For well-differentiated thyroid cancer, TSH is generally suppressed to less than 0.1 mU/L. Doses of levothyroxine greater than 2 µg/kg/day are usually required. The efficacy of TSH suppression in reducing the size of benign thyroid nodules and in preventing nodule regrowth after surgery is controversial. Nevertheless, when treatment with levothyroxine is warranted, TSH is generally suppressed to a higher target range (e.g., 0.1 to 0.3 mU/L) than that employed for the treatment of thyroid cancer. Levothyroxine therapy may also be considered for patients with nontoxic multinodular goiter who have a TSH in the normal range, to moderately suppress TSH (e.g., 0.1 to 0.3 mU/L).

Levothyroxine should be administered with caution to patients in whom there is a suspicion of thyroid gland autonomy, in view of the fact that the effects of exogenous hormone administration will be additive to endogenous thyroid hormone production.

Pediatric Dosage: Congenital or acquired hypothyroidism: The levothyroxine pediatric dosage varies with age and body weight. Levothyroxine should be given at a dose that maintains T 4 or free T 4 in the upper half of the normal range and serum TSH in the normal range (See Precautions, Children). Normalization of TSH may lag significantly behind T 4 in some infants. In general, despite the smaller body size of children, the dosage (on a weight basis) required to sustain full development and general thriving is higher than in adults. See Table I.

Therapy is usually initiated at the full replacement dose (see Table I). Infants and neonates with very low (<5 µg/dL) or undetectable serum T 4 levels should be started at higher end of the dosage range (e.g., 50 µg daily). A lower dose (e.g., 25 µg daily) should be considered for neonates at risk of cardiac failure, increasing every few days until a full maintenance dose is reached. In children with severe, longstanding hypothyroidism, levothyroxine should be initiated gradually, with an initial 25 µg dose for 2 weeks, then increasing by 25 µg every 2 to 4 weeks until the desired dose, based on serum T 4 and TSH levels, is achieved.

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Table I--Synthroid

Dosage Guidelines for Pediatric Hypothyroidism

Age Daily dose/kg of body weight (µg)*

0-3 months 3-6 months 6-12 months 1-5 years 6-12 years >12 years Growth and puberty complete 10-15 8-10 6-8 5-6 4-5 2-3 1.6

*To be adjusted on the basis of clinical response and laboratory tests (see Precautions, Children).

Serum T 4 and TSH measurements should be evaluated at the following intervals, with subsequent dosage adjustments to normalize serum total T 4 or FT 4 and TSH: 2 and 4 weeks after therapy initiation, every 1 to 2 months during the first year of life, every 2 to 3 months between 1 and 3 years of age, every 3 to 12 months thereafter until growth is completed.

Evaluation at more frequent intervals is indicated when compliance is questioned or abnormal laboratory values are obtained. Patient evaluation is also advisable approximately 6 to 8 weeks after any change in levothyroxine dose.

Levothyroxine 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 non-soybean based formula. 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 apple sauce. Foods or formula containing large amounts of soybean, fibre, or iron should not be used for administering levothyroxine.

Injection: Directions for Reconstitution: Reconstitute the lyophilized levothyroxine sodium by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only. Do not use bacteriostatic sodium chloride injection, USP, as the bacteriostatic agent may interfere with complete reconstitution. Shake vial to ensure complete mixing. Use immediately after reconstitution. Do not add to other fluids. Discard any unused portion.

Availability And Storage:

Injection: Each vial of sterile lyophilized powder contains: levothyroxine sodium, USP 500 µg. Nonmedicinal ingredients: mannitol USP, sodium hydroxide and tribasic sodium phosphate (anhydrous). Single dose color-coded (yellow) vials of 10 mL. Store at controlled room temperature 15 to 30°C.

Tablets: 25 µg: Each orange, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 25 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

50 µg: Each white, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 50 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

75 µg: Each violet, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 75 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, FD&C Blue No. 2, FD&C Red No. 40, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

88 µg: Each olive, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 88 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, FD&C Yellow No. 10, FD&C Blue No. 1, FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

100 µg: Each yellow, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 100 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, FD&C Yellow No. 10, FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

112 µg: Each rose, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 112 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, D&C Red No. 27 & 30, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

125 µg: Each brown, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 125 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

150 µg: Each blue, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 150 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, FD&C Blue No. 2, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

175 µg: Each lilac, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 175 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, D&C Red No. 27 & 30, FD&C Blue No. 1, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

200 µg: Each pink, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 200 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, FD&C Red No. 40, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

300 µg: Each green, round, color-coded, scored tablet, debossed with "FLINT" and potency contains: levothyroxine sodium 300 µg. Nonmedicinal ingredients: acacia, confectioner's sugar, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc. Bottles of 100 and 1 000.

Store at controlled room temperature 15 to 30°C. Protect from light and moisture.