0.025 mg / 0.037 mg / 0.050 mg / 0.062 mg / 0.075 mg / 0.088 mg
0.100 mg / 0.112 mg / 0.125 mg / 0.137 mg / 0.150 mg / 0.175 mg
0.200 mg / 0.250 mg / 0.300 mg
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
Each LEVOTHYROXINE SODIUM TABLETS USP contains synthetic crystalline Levothyroxine sodium (L-thyroxine). L-thyroxine is the principle hormone secreted by the normal thyroid gland. Chemically, L-thyroxine is designated as L-tyrosine, 0-( 4-hydroxy-3, 5-diiodophenyl ) – 3, 5-diiodo-, monosodium salt, hydrate. The molecular formula is C15H10I4N NaO4 .XH20 and the structural formula is :
CLINICAL PHARMACOLOGY :
The principal effect of thyroid hormones is to increase the metabolic rate of most body tissues. The thyroid hormones are also concerned with growth and development of tissues in the young and are particularly important for the developing nervous system. The major thyroid hormones are L-thyroxine (T4) and L-triiodothyronine (T3). The amounts of T4 and T3 released from the normally functioning thyroid gland are regulated by the amount of thyrotropin (TSH) secreted from the anterior pituitary gland. T4 is the major component of normal thyroid gland secretions and is therefore the primary determinant of normal thyroid functions. T4 acts as a substrate for physiologic deiodination to T3 in the peripheral tissues. The physiologic effects of thyroid hormones are largely mediated at the cellular level primarily by T3. LEVOTHYROXINE SODIUM TABLETS USP taken orally provide T4 which upon absorption cannot be distinguished from T4 secreted endogenously. Oral T4 is absorbed in the small intestine, mainly in the jejunum and ileum; about two-thirds to three-quarters of the oral dose is actually absorbed. Absorption may be less than expected in patients with malabsorptive bowel disease, such as sprue, or with short bowel syndromes. Absorption is also affected by food and is slightly higher in the fasting state compared to when an oral dose is taken with food; the difference, however, is usually not of much clinical consequence. Certain other medications taken concomitantly by mouth can diminish absorption of T4 from the intestinal lumen; these include aluminium hydroxide, sucralfate, ferrous sulfate, soybean-based foods (often taken for medical reasons), and binding resins used to lower serum cholesterol.
Once in the blood stream, T4 is bound to plasma proteins, mainly to thyroxine-binding globulin (TBG); neverthless, T4 gains access to the tissues where it acts because the small fraction of T4 that is not bound to plasma proteins (“free T4”) does cross cell membranes. A small fraction of circulating T4 is also converted to circulating triiodothyronine (T3), mainly in the liver; T3 is also largely bound to circulating plasma proteins but not as tightly as is T4. Once inside responsive cells, T4 is converted to T3 which is the major thyroid hormone acting intracellularly; circulating T3 also gains access to the intracellular space and contributes to the action of thyroid hormone.
Circulating T4 is gradually eliminated from the body with a plasma half-life of about seven days. Thus, an oral dose given once daily, once the dose is stabilized, results in a fairly stable level of serum T4 over the course of the next 24 hours except for a slight rise of 10% to 15% in the few hours after the oral dose. The circulating T3 formed from circulating T4, on the other hand, is cleared from the blood much more rapidly with a plasma half-life of about 1 to 1 ½ days. Thus, the oral dosing of T4 results in a steady, stable serum level of T4 which in turn provides an equally stable level of serum T3. Oral T3 given alone, on the other hand, results in a fairly rapid rise and fall in the serum T3 level after each dose and fails to mimic the normal pattern of serum T3.
INDICATIONS AND USAGE :
LEVOTHYROXINE SODIUM TABLETS USP are indicated for :
1. Replacement therapy for any form of diminished or absent thyroid function, e.g., as in cretinism, myxedema, or hypopituitarism, and including hypothyroidism seen in children, in pregnancy and in the elderly. The hypothyroidism may result from functional deficiency, primary atrophy, or partial or complete absence of the thyroid gland; from the effects of surgery, radiation or antithyroid agents on the thyroid gland; or from pituitary or hypothalamic disease. LEVOTHYROXINE SODIUM TABLETS USP therapy must usually be maintained continuously to control the hypothyroidism. When hypothyroidism is due to subacute or postpartum thyroiditis, it may be temporary and treatment need not be permanent.
2. A means of suppressing pituitary secretion of TSH in euthyroid patients in order to treat or prevent the recurrence of various types of goiter, including thyroid nodules, lymphocytic thyroiditis (Hashimoto’s), multinodular goiter, and as part of the management of thyroid cancer. An exception is a patient with euthyroid autonomous function wherein the goiter is not under the control of pituitary TSH; T4 therapy is not indicated in such patients (see below under CONTRAINDICATIONS).
3. A diagnostic agent in suppression tests to aid in the diagnosis of suspected mild hyperthyroidism or thyroid gland autonomy; this should be done rarely, only when clinically indicated and only when other tests such as stimulation with thyrotropin-releasing hormone (TRH) have not resolved the problem.
L-thyroxine therapy is contraindicated in untreated thyrotoxicosis, in other states of thyroid autonomy, acute myocardial infarction and uncorrected adrenal insufficiency.
Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been 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.
Caution must be exercised in the administration of this drug to patients with cardiovascular disease. Development of chest pain or other aggravation of the cardiovascular disease may preclude its use or require a reduction of dosage in treated patients (see also DRUG INTERACTIONS). Institution of levothyroxine therapy in patients with adrenal insufficiency requires concomitant glucocorticoid therapy.
Information For The Patient :
Patients taking LEVOTHYROXINE SODIUM TABLETS USP and parents of children taking LEVOTHYROXINE SODIUM TABLETS USP should be informed that:
1. Replacement therapy is to be taken essentially for life, with the exception of cases of transient hypothyroidism, usually associated with thyroiditis, and in those patients receiving a therapeutic trial of the drug.
2. During the course of therapy, they should immediately report any signs or symptoms of thyroid hormone toxicity, e.g., chest pain, increased pulse rate, palpitations, excessive sweating, heat intolerance, nervousness, or any other unusual event.
3. In case of concomitant diabetes mellitus, the daily dosage of antidiabetic medication may need readjustment as thyroid hormone replacement is achieved. If LEVOTHYROXINE SODIUM TABLETS USP are stopped, a downward readjustment of the dosage of insulin or oral hypoglycemic agent may be necessary to avoid hypoglycemia. Monitoring of urinary or blood glucose levels is mandatory in such patients during changes in thyroid medication.
4. In case of concomitant oral anticoagulant therapy, the prothrombin time should be measured frequently to determine if the dosage of oral anticoagulants is to be readjusted.
5. Patients taking LEVOTHYROXINE SODIUM TABLETS USP who then become pregnant should be monitored closely with measurements of serum TSH concentration because the requirement for T4 usually increases during pregnancy. The daily dose of LEVOTHYROXINE SODIUM TABLETS USP may need to be increased to maintain the serum TSH concentration within the normal reference range.
6. Partial loss of hair may be experienced in the first few months of thyroid therapy, but this is usually a transient phenomenon and later recovery is the rule.
Laboratory Tests :
The patient’s response to thyroid replacement can be followed by laboratory tests such as serum levels of thyroxine (T4), serum triiodothyronine (T3), free thyroxine index and thyroid stimulating hormone (TSH). The principal test used to monitor treatment in primary hypothyroidism is the serum TSH level. In hypopituitarism, the serum TSH level is not useful and monitoring should be done with measurement of serum total or free T4. In euthyroid goiter patients or those with thyroid cancer, the serum TSH should be suppressed below the reference range; how far below the reference range depends on the clinical goal.
Drug Interactions :
In patients with diabetes mellitus, addition of oral T4 therapy may cause an increase in the required dosage of insulin or oral hypoglycemic agents. Therefore, patients with diabetes mellitus should be observed closely for possible changes in antidiabetic drug dosage requirements. Patients stabilized on oral anticoagulants who are found to require thyroid replacement therapy should be watched very closely when therapy is started; successful treatment with LEVOTHYROXINE SODIUM TABLETS USP in a patient who is initially hypothyroid may result in a need for a lower dose of oral anticoagulant. No special precautions appear to be necessary when oral anticoagulant therapy is begun in a patient already stabilized on maintenance LEVOTHYROXINE SODIUM TABLETS USP therapy. Cholestyramine and colestipol bind T4 in the intestine, thus impairing its absorption. In vitro studies indicate that the binding is not easily reversed. Therefore, four to five hours should elapse between administration of cholestyramine and oral T4. Other medications that interfere with absorption of oral T4 from the gut include sucralfate, ferrous sulfate, aluminium hydroxide and soy-containing dietary supplements.
Estrogens tend to increase serum thyronine-binding globulin (TBG). In a patient with a non-functioning thyroid gland who is receiving thyroid replacement therapy, free thyroxine may be decreased when estrogens are started thus increasing LEVOTHYROXINE SODIUM TABLETS USP requirements. Therefore, patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their dosage of LEVOTHYROXINE SODIUM TABLETS USP if estrogens or estrogen-containing oral contraceptives are given. This need can be assessed by measurement of the serum TSH level. Similarly, androgen therapy in hypogonadal men, or women with breast cancer, can decrease TBG; the result may be a decreased need for oral T4 and so the dosage of LEVOTHYROXINE SODIUM TABLETS USP may need to be decreased. Again, measurement of the serum TSH level is a good method of assessing this possibility.
Drug/Laboratory Test Interactions :
The following drugs or moieties are known to interfere with laboratory tests performed on patients taking thyroid hormone: androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-containing preparations, and salicylates. In some instances, e.g., the use of androgens, estrogens, or oral contraceptives, patients’ thyroid status may be affected and monitoring with serum TSH measurement may be indicated.
1. Pregnancy, estrogens and estrogen - containing oral contraceptives increase TBG concentrations. TBG may also be increased during infectious hepatitis. Decreases in TBG concentrations can occur in nephrosis, acromegaly, or during androgen or corticosteroid therapy. Familial hyper- or hypo-thyroxine-binding-globulinemias have been described. The binding of thyroxine by thyroid-binding pre-albumin (TBPA) is inhibited by salicylates. In all these cases of changes in L-T4 binding to serum proteins, the serum T4 level may change. Measurement of the serum TSH level will determine the clinical significance of any change in serum T4.
2. A high iodine intake interferes with radio-iodine uptake (RAIU) in normal persons but the RAIU would be low in those taking thyroxine in any case; this test has little use in patients treated with oral T4 and the interference of a high iodine intake is of little clinical relevance.
3. Continued evidence of hypothyroidism in spite of apparently adequate dosage replacement indicates poor patient compliance, poor absorption, excessive fecal loss, interference by concomitantly ingested food, or inactivity of the preparation. Poor compliance is the most common cause but each possible cause should be considered.
Carcinogenesis, Mutagenesis, And Impairment Of Fertility :
A reportedly apparent association between prolonged thyroid therapy and breast cancer has not been confirmed and patients taking LEVOTHYROXINE SODIUM TABLETS USP for established indications should not discontinue therapy. There are no data suggesting that L-T4 is mutagenic or impairs fertility; such studies in animals over the long term have not been performed.
Pregnancy : Category A
Thyroid hormones do not readily cross the placental barrier. Clinical experience to date does not indicate any adverse effect on fetuses when thyroid hormones are administered to pregnant women. On the basis of current knowledge, LEVOTHYROXINE SODIUM TABLETS USP replacement therapy to hypothyroid women should not be discontinued during pregnancy. During pregnancy, LEVOTHYROXINE SODIUM TABLETS USP requirements may increase; dosage should be guided by periodic measurement of serum TSH concentration.
Nursing Mothers :
Some thyroid hormone is excreted in human milk but this is usually insufficient for hypothyroid nursing neonates. L-T4 taken by nursing mothers is not associated with serious adverse reactions and does not have a known tumorigenic potential; properly indicated LEVOTHYROXINE SODIUM TABLETS USP therapy should be continued.
Paediatric Use :
Congenital hypothyroidism is uncommon (1:4,000) and is not prevented by the small amounts of hormone that cross the placenta. Determination of serum T4 and/or TSH is needed to make the diagnosis in neonates and must be done within a few days of birth to prevent the serious effects of hypothyroidism on growth and development, particularly of the brain and nervous system. Treatment should be initiated immediately upon diagnosis, and maintained for life, unless transient hypothyroidism is suspected in which case therapy may be interrupted for 2 to 8 weeks after the age of 3 years to reassess the condition. Cessation of therapy is justified in patients who have maintained a normal TSH during those 2 to 8 weeks.
ADVERSE REACTIONS :
Adverse reactions are due to overdosage and are those of induced hyperthyroidism.
Excessive dosage of thyroid medication may result in symptoms of hyperthyroidism. Since, however, the effects do not appear at once, the symptoms may not appear for one to three weeks after an excessive dose is begun. The most common signs and symptoms of overdosage are weight loss, palpitation, nervousness, diarrhea or abdominal cramps, sweating, tachycardia, cardiac arrhythmias, angina pectoris, tremors, headache, insomnia, and intolerance to heat. If symptoms of overdosage appear, discontinue the medication for several days and reinstitute treatment at a lower dosage level. Laboratory tests such as serum T4, serum T3 and the free thyroxine index will be elevated during the period of overdosage and the hallmark is a clearly suppressed serum TSH level. Complications as a result of the induced hypermetabolic state may include, cardiac failure and death due to arrhythmia or failure.
TREATMENT OF OVERDOSAGE :
Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted at a lower dosage. Treatment of acute massive thyroid hormone overdosage is aimed at reducing gastrointestinal absorption of the drugs and counteracting central and peripheral effects, mainly those of increased sympathetic activity. Vomiting may be induced initially if further gastrointestinal absorption can reasonably be prevented provided there are no contraindications such as coma, convulsions, or loss of the gag reflex. Treatment is mainly symptomatic and supportive. Oxygen may be administered and ventilation maintained. Cardiac glycosides may be indicated if congestive heart failure develops. Measures to control fever, hypoglycemia, or fluid loss should be instituted if needed. Antiadrenergic agents, particularly propranolol, have been used advantageously in the treatment of increased sympathetic activity. Propranolol may be administered intravenously at a dosage of 1 to 3 mg over a 10 minute period or orally, 80 to 160 mg/day, especially when no contraindications exist for its use.
Primary Hypothyroidism :
The goal of therapy in primary hypothyroidism should be the restoration of euthyroidism as judged by clinical response and confirmed by appropriate laboratory tests such as serum thyroxine (T4), serum triiodothyronine (T3), free thyroxine index and serum TSH; the principal measure in primary hypothyroidism is the serum TSH level. The age and general condition of the patient, the severity and duration of hypothyroid symptoms, and whether or not the serum TSH level remains high or has become normal determine the starting dose of LEVOTHYROXINE SODIUM TABLETS USP and the rate of incremental dosage leading to a final maintenance dosage.
In otherwise healthy adults with primary hypothyroidism, the recommended initial dosage of LEVOTHYROXINE SODIUM TABLETS USP is 0.025 to 0.1 mg daily, while the predicted full maintenance dose of 0.1 to 0.2 mg daily may be achieved in several months. In the elderly patient with primary hypothyroidism, particularly in those with long-standing or severe primary hypothyroidism or with evidence of cardiovascular dysfunction, the initial dose of LEVOTHYROXINE SODIUM TABLETS USP may be as little as 0.0125 mg per day; incremental increases of 0.025 mg per day at 4 to 6 week intervals may be instituted depending on patient response. It is the physician’s judgement of the severity of the disease and close observation of patient response and of the serum TSH level which determine the rate and extent of dosage increase.
Once the serum TSH level in those with primary hypothyroidism has fallen to the normal reference range during LEVOTHYROXINE SODIUM TABLETS USP treatment and the serum TSH concentration has been stable at this level for 4 to 8 weeks, the daily dose being taken is then the maintenance dose. To monitor the adequacy of this dose and patient compliance, periodic assessment of the serum TSH level should be done. The aim is the maintenance of the serum TSH level in the normal reference range. There are no data showing the optimum frequency of measurement of serum TSH concentration in this circumstance but common practice is 1 to 3 times per year; if there is reason to suspect poor compliance with therapy or other potential problems, the serum TSH measurement should be done more often, even when the dose of oral T4 is unchanged.
Severe Hypothyroidism :
Sometimes referred to as “myxedema coma”, far-advanced hypothyroidism is an uncommon but dangerous and potentially lethal state. Often precipitated by another event, such as infection or injury, in an already hypothyroid patient and often characterized by hypothermia and somnolence or actual coma, severe hypothyroidism is a medical emergency. Other characteristics are slow pulse, electrolyte abnormalities such as hyponatremia, respiratory failure with CO2 retention, and hypotension. The principal treatment initially is aimed at supportive therapy, treatment of infection if present, gentle warming if indicated, and correction of non-thyroid abnormalities such as abnormal electrolyte values or cardiac arrhythmias. Glucocorticoid therapy is often given, although there are no data showing clear benefit. In addition, replacement therapy with levothyroxine is essential. While oral T4 appears to be well absorbed in such patients, there are no data showing in a controlled trial whether it is better to give the L-T4 by month, by nasogastric tube, or parenterally. Neverthless, many prefer to give the L-T4 parenterally. Similarly, there is no clear consensus on the dose of L-T4 to be used; some prefer to give enough to replace the entire deficiency of circulating T4 0.4 to 0.6 mg, usually parenterally, as a single dose or given over a few hours) while other physicians prefer to begin with smaller doses, e.g., 0.075-0.15 mg given by mouth, if possible, or parenterally, if not. Further dosing of L-T4 depends on patient response which in turn requires intensive monitoring for at least a few days. The total daily dose of L-T4 given after the initial dose should in general not exceed the daily dose required previously by the patient or the average daily dose taken by similar patients. Clinical judgement is a major determinant of the details of treatment because laboratory results will usually not be available initially.
Secondary Hypothyrodism :
Hypothyroidism due to pituitary or hypothalamic disease, or secondary hypothyroidism, is uncommon; the vast majority of hypothyroid patients have primary hypothyroidism. Secondary hypothyroidism is suspected whenever there is known hypothalamic or pituitary disease, such as pituitary tumor or diabetes insipidus; it is characterized by a low serum concentration of total T4 or free T4 without a clearly raised serum TSH concentration; the serum TSH level may be slightly raised, in the reference range, or low. The serum TSH level cannot be used to monitor the dosage of LEVOTHYROXINE SODIUM TABLETS USP as it is in primary hypothyroidism. The initial dose of LEVOTHYROXINE SODIUM TABLETS USP should be chosen as it is in primary hypothyroidism, observing the same guidelines and precautions (see Primary Hypothyroidism). Further dose increases, if any, are based on the clinical response using clinical judgement and measurement of serum total or free T4.
Suppression of Pituitary Secretion of TSH :
In selected patients with goiter, thyroid nodules, or papillary or follicular thyroid cancer, LEVOTHYROXINE SODIUM TABLETS USP can be used in an attempt to inhibit growth or prevent re-growth of the abnormal thyroid tissue; the overall management may include other therapies such as surgery or radioactive iodine. The suppressive action of LEVOTHYROXINE SODIUM TABLETS USP is based on the known ability of oral T4 to suppress pituitary secretion of TSH even when patients are initially euthyroid (a hypothyroid person with any of the above conditions should be treated with LEVOTHYROXINE SODIUM TABLETS USP in any case for the hypothyroidism). Because most persons with these conditions are euthyroid and so have a normal serum TSH concentration, the goal of LEVOTHYROXINE SODIUM TABLETS USP therapy is to suppress the serum TSH level to below the reference range. In so doing, some patients with these conditions may have an inhibition of further growth of the abnormal thyroid tissue. Because various clinical trials have reached different conclusions on the efficacy of oral T4 in the treatment of thyroid nodules or goiter and there are no controlled trials on its use in papillary or follicular thyroid cancer or on the degree to which the serum TSH level needs to be suppressed, the use of LEVOTHYROXINE SODIUM TABLETS USP in these conditions needs to be individualized; continued use depends on the clinical response balanced against the possibility of induced hyperthyroidism. In general, the suppression of serum TSH concentration should be to the level of 0.1 to 0.2 mU/L although some prefer to suppress the serum TSH concentration to less than 0.1 mU/L in patients with differentiated thyroid carcinoma.
Paediatric Hypothyroidism :
In infants and children there is a great urgency to achieve full thyroid replacement because of the critical importance of thyroid hormone in sustaining growth and maturation as well as development of the brain and intellectual function. Despite the smaller body size, the dosage needed to sustain a full rate of growth, development and general thriving is higher in the child than in the adult. The recommended daily replacement dosage of L-thyroxine in childhood is: 0-6 months : 8-10 mcg/kg; 6-12 months : 6-8 mcg/kg; 1-5 years: 5-6 mcg/kg; 6-12 years: 4-5 mcg/kg of body weight daily.
HOW SUPPLIED :
LEVOTHYROXINE SODIUM TABLETS USP are supplied as follows :
1. 0.025 mg/tablet
2. 0.037 mg/tablet
3. 0.050 mg/tablet
4. 0.062 mg/tablet
5. 0.075 mg/tablet
6. 0.088 mg/tablet
7. 0.100 mg/tablet
8. 0.112 mg/tablet
9. 0.125 mg/tablet
10. 0.137 mg/tablet
11. 0.150 mg/tablet
12. 0.175 mg/tablet
13. 0.200 mg/tablet
14. 0.250 mg/tablet
15. 0.300 mg/tablet
Store at controlled room temperature 15–30O C (59-86O F), in a dry place.protected from light.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.