Action And Clinical Pharmacology: Levothyroxine sodium is the monosodium salt of the levorotatory isomer of thyroxine (tetraiodothyronine), the principal hormone secreted by the normal thyroid gland.

Pharmacokinetics: Following oral administration, the absorption of levothyroxine is incomplete and variable (50 to 75%), especially when taken with food. Once absorbed, synthetic levothyroxine is indistinguishable from the endogenous hormone.

Levothyroxine is nearly totally bound to serum proteins and has an elimination half-life of 6 to 7 days in the euthyroid subject. Half-life is shortened in hyperthyroidism and prolonged in hypothyroidism and in pregnancy. Deiodination of levothyroxine (T4) to 1-triiodothyronine (T3) occurs in various tissues, particularly liver and kidney. T3 is approximately 4 times as potent as T4 on a weight basis.

The mechanism of action of thyroid hormones is not completely understood. The principle effect is to increase the metabolic rate of body tissues. Thyroid hormones have both catabolic and anabolic effects, and are therefore involved in normal metabolism, growth, and development, especially the development of the CNS in infancy.

Indications And Clinical Uses: Specific hormonal replacement therapy in the presence of hypothyroidism of any etiology.

Contra-Indications: Patients with hypersensitivity to any ingredient of the tablets and patients with thyrotoxicosis, acute myocardial infarction or uncorrected adrenal insufficiency. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Lactation: In euthyroid lactating mothers, levothyroxine (endogenous or exogenous) may be secreted into breast milk in amounts sufficient to mask signs of hypothyroidism in the nursing infant.

The use of levothyroxine in the treatment of obesity in patients who are not hypothyroid has been shown to be ineffective and potentially harmful.

Precautions: Pregnancy: Levothyroxine does not readily cross the placenta, and when successfully employed to render or maintain the patient in an euthyroid state, therapy is considered to be warranted in pregnant patients. Hypo- or hyperthyroid activity in the mother may unfavorably influence the fetal outcome or well being. Due to the profound effects of thyroid hormones on energy-requiring metabolic processes, the administration of levothyroxine to a hypothyroid patient may unmask occult cardiovascular, endocrine or metabolic disease. Long standing hypothyroidism is associated with atherogenesis, which may or may not manifest itself in the hypometabolic state. In such cases levothyroxine should be administered with extreme caution employing low initial dosage increased slowly by small increments, as even a gradual restoration of normal metabolic rate may result in development or exacerbation of myocardial ischemia and angina. In some patients, cardiovascular status may be so compromised that the metabolic demands of the euthyroid state cannot be met, despite the employment of appropriate antianginal therapy. Clinical judgment may then dictate a less-than-complete restoration of thyroid status. Endocrine disorders such as diabetes mellitus, diabetes insipidus, Addison's disease (adrenal insufficiency) and hypopituitarism are characterized by signs and symptoms which may be diminished in severity or obscured by hypothyroidism. Treatment with levothyroxine may require that appropriate adjustments in therapy for these concomitant disorders be made. In particular, when hypothyroidism is accompanied by adrenal insufficiency (such as in panhypopituitarism), appropriate adrenocortical replacement therapy should be instituted prior to commencement of treatment with levothyroxine in order to prevent the possible precipitation of Addisonian crisis. Slightly excessive dosage of thyroid agents were previously recommended for replacement therapy in congenital hypothyroidism (cretinism), since it was thought that slight underdosage was harmful while slightly excessive dosage was not. However, it is currently recommended that excessive dosage be avoided since minimal brain damage has occurred in children with thyrotoxicosis during infancy and excessive dosage may accelerate bone age and cause premature craniosynostosis (see Dosage). The intestinal absorption of levothyroxine may be impaired in patients with certain malabsorption states, particularly celiac sprue (gluten enteropathy). Higher dosages of levothyroxine may be required in such patients, especially during exacerbations of the enteropathy. Levothyroxine should be used with caution in elderly patients who may be more sensitive to the effects of thyroid hormones (see Dosage). Due to potential differences in potency and bioavailability, different levothyroxine products may not be interchangeable. Patients stabilized on a particular brand of levothyroxine should not be unnecessarily switched to another brand. When such a brand change is necessary, the patients must be carefully re-evaluated to assess the potential need for dosage adjustment.

Dosage And Administration: Dosage of levothyroxine must be carefully adjusted according to individual requirements and response. The age and general physical condition of the patients and the severity and duration of hypothyroid symptoms determine the initial dosage and rate at which dosage may be increased to the eventual maintenance dosage (see Precautions). Adjustment of levothyroxine dosage should be based mainly on the patient's clinical response and confirmed by appropriate laboratory tests. Laboratory tests alone should not be relied upon to guide therapy. For purposes of conversion, levothyroxine sodium (T4) 100 µg is usually considered equivalent to desiccated thyroid 60 mg, thyroglobulin 60 mg, or liothyronine sodium (T3) 25 µg. However, these are rough guidelines only and do not obviate the careful re-evaluation of a patient when switching thyroid hormone preparations, including a change from one brand of levothyroxine to another (see Precautions). Information for the Patient: Patients on thyroid preparations and parents of children on thyroid therapy should be informed that 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. Patients should immediately report to the physician experiences during the course of therapy of 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. Patients with concurrent diabetes mellitus or who are on concurrent oral anticoagulant therapy should be warned of the need for close monitoring and possible dosage adjustments. Parents should be warned that 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 normally the rule. Adults: For the management of mild hypothyroidism, the usual initial dose is 50 µg once daily. Dosage may be increased in increments of 25 to 50 µg/day at intervals of 2 to 4 weeks until the desired response is obtained. For the management of severe hypothyroidism the usual initial dosage is 12.5 to 25 µg once daily. Dosage may be increased by increments of 25 to 50 µg/day at intervals of 2 to 4 weeks until the desired response is obtained. The usual maintenance dosage for full replacement therapy is 100 to 200 µg/day, although certain patients may require higher dosages. Failure to respond adequately to dosages exceeding 300 to 400 µg/day is rare and should prompt re-evaluation of the diagnosis, or suggest the presence of malabsorption or patient noncompliance. For geriatric patients with hypothyroidism, the usual initial dosage is 12.5 to 50 µg once daily. Dosage may be increased at intervals of 3 to 8 weeks until the desired response is obtained. Thyroid hormone replacement requirements are about 25% lower in patients over the age of 60 years than in younger adults. Infants and Children: In infants and children, it is essential to achieve rapid and complete thyroid replacement because of the critical importance of thyroid hormones in sustaining growth and maturation, including the normal development of the CNS. In general, the dosage requirements of children, on a per body weight basis, are higher than those of adults. Premature neonates weighing less than 2 kg and neonates at risk of cardiac failure may receive an initial dosage of 25 µg once daily; dosage may be increased to 50 µg once daily in 4 to 6 weeks.