LEVOTEC
Technilab
Levothyroxine Sodium
Hypothyroidism Therapy
Action And Clinical Pharmacology: Levothyroxine sodium is the monosodium salt of the levorotatory isomer of thyroxin (tetraiodothyronine), the principal hormone secreted by the normal thyroid gland.
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 principal 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 or supplemental therapy in the presence of hypothyroidism of any etiology, with the exception of transient hypothyroidism during the recovery phase of subacute thyroiditis.
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 disease), multinodular goiter and in the management of thyroid cancer.
As a diagnostic agent in suppression tests to aid in the diagnosis of suspected mild hyperthyroidism or thyroid gland autonomy.
Contra-Indications: Patients with hypersensitivity to any of the active or extraneous constituents of the tablets, and in patients with thyrotoxicosis, acute myocardial infarction or uncorrected adrenal insufficiency.
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 suckling infant.
The use of levothyroxine, along or combined with other drugs, in the treatment of obesity or infertility in patients who are not hypothyroid has been shown to be ineffective and potentially harmful. In the treatment of obesity with hypothyroidism, large 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.
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.
Lactation: Minimal amounts of thyroid hormones are secreted in human milk. Although thyroid hormones are not associated with serious adverse reactions and does not have known tumorigenic potential, caution should be exercised when therapy is administered to nursing patients. Generally however, adequate replacement doses of levothyroxine are needed to maintain normal lactation.
Children: 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 in order to reassess their condition. Cessation of therapy is justified in patients who have maintained a normal TSH during those 2 to 8 weeks.
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.
Hypothyroidism of long standing is associated with atherogenesis, which may or may not fully 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.
Hypothyroidism decreases the sensitivity to oral anticoagulants. Prothrombin time should be closely monitored in thyroid treated patients on oral anticoagulants and dosage of the latter agents adjusted on the basis of frequent prothrombin time determinations. In infants, excessive doses of thyroid hormone preparations may produce craniosynostosis.
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.
Geriatrics: Levothyroxine should be used with caution in elderly patients who may be more sensitive to the effects of thyroid hormones (see Dosage).
Drug Interactions: Thyroid hormones potentiate the hypoprothrombinemic effects of oral anticoagulant agents such as warfarin. When treatment with levothyroxine is initiated in patients receiving oral anticoagulants, the prothrombin time should be determined frequently and the anticoagulant dosage reduced appropriately.
Administration of levothyroxine to a diabetic patient may result in an increase in the patient’s requirements for insulin and/or hypoglycemic medication (see above).
Cholestyramine resin binds levothyroxine in the intestinal tract and substantially impairs its absorption. When the two agents must be used concurrently the levothyroxine dose should be taken at least 1 hour before or 4 hours after the dose of cholestyramine, with regular monitoring of thyroid function.
Phenytoin competes with thyroid hormones for serum protein binding sites, resulting in an increase in the unbound fractions of T3 and T4 and an enhanced thyroid effect. Dosage reduction may be necessary in sensitive patients.
Administration of phenytoin to patients stabilized on levothyroxine may necessitate a reduction in the dosage of the latter.
Phenobarbital induces hepatic enzymes and increases the rate of degradation of thyroid hormones. The dosage of levothyroxine may need to be increased when concurrent therapy with phenobarbital is employed.
Beta-adrenergic blocking agents may decrease peripheral conversion of T4 to T3, thereby reducing the efficacy of exogenous levothyroxine.
Estrogens increase serum thyroxin-binding globulin levels, thereby decreasing the unbound fractions of T3 and T4. Administration of estrogen-containing preparations (such as oral contraceptives) to hypothyroid patients may cause an increase in their levothyroxine requirements.
Patients receiving thyroid replacement therapy who undergo anesthesia with ketamine should be closely monitored for possible hypertension and tachycardia.
Concurrent use of sympathomimetic agents or tricyclic antidepressants with thyroid hormones may result in enhanced effects of either medication. In patients with coronary artery disease receiving thyroid replacement therapy, administration of sympathomimetic agents increases the risk of coronary insufficiency.
If coadministered with cardiac glycosides, adjustment of dosage of cardiac glycoside may be necessary.
Laboratory Test Interactions : Various physiologic and pathologic conditions or certain drugs can interfere with thyroid function tests and their interpretation. Serum thyroxin-binding globulin (TBG) is increased in pregnancy, on estrogen therapy, or in patients using estrogen-containing oral contraceptives. Infectious hepatitis may also increase serum TBG concentration. Decreased TBG is found in patients on androgen or corticosteroid therapy and also in cases of nephrosis and acromegaly. Some drugs such as phenylbutazone and salicylates bind competitively to TBG or thyroxin-binding prealbumin. Familial hyper- or hypo-thyroxin-binding globulinemias have been reported.
Adverse Reactions: Adverse reactions to levothyroxine are confined to hypersensitivity to or intolerance of an ingredient of the tablets, and toxicity due to overdosage of levothyroxine (see Overdose: Symptoms and Treatment).
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage with levothyroxine can be expected to produce the typical signs and symptoms of thyrotoxicosis. These may include weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressures, angina pectoris, cardiac dysrhythmias, tremors, headache, insomnia, heat intolerance, fever and dysmenorrhea.
Severe overdosage is equivalent to thyroid storm and may be manifested by coma, cardiac decompensation, and possibly death secondary to cardiac dysrhythmia or failure. The effects of acute overdosage of levothyroxine may take several days to appear.
The manifestations of levothyroxine overdosage should be managed by discontinuation of levothyroxine for 2 to 7 days followed by resumption of treatment with lower doses.
The management of acute severe overdosage should consist principally of reducing absorption of the drug and counteracting central and peripheral effects, mainly those of increased sympathetic nervous activity. Initially, the stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of vomitus. Oxygen may be administered and ventilation maintained. If congestive heart failure develops, cardiac glycosides may be administered. Measures to control fever, hypoglycemia, or fluid loss should be initiated as necessary. A b-adrenergic blocking agent may be useful to counteract many of the effects of increased sympathetic activity. Provided no contraindications for its use exist, propranolol may be administered i.v. in a dosage of 1 to 3 mg every 10 minutes, or orally in a dosage of 80 to 100 mg/day. However, propylthiouracil and other antithyroid agents are not effective in the treatment of thyrotoxicosis due to overdosage of exogenous levothyroxine.
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.
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.
Geriatrics: 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. Levothyroxine tablets may be given to infants and children unable to swallow intact tablets by crushing the appropriate dose and suspending it in a small amount of water or formula, in cooked cereal or apple sauce. Do not store the suspension for any period of time.
Prematures: 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.
Availability And Storage: 25 µg: Each round, orange, scored tablet, engraved with 25 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 25 µg. Nonmedicinal ingredients: dibasic calcium phosphate, D&C Yellow #10, FD&C Red #40, starch, stearic acid, and talc. Bottles of 100 and 1 000.
50 µg: Each round, white, scored tablet engraved with 50 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 50 µg. Nonmedicinal ingredients: dibasic calcium phosphate, starch, stearic acid, and talc. Coloring agents-free. Bottles of 100 and 1 000.
75 µg: Each round, violet, scored tablet, engraved with 75 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 75 µg. Nonmedicinal ingredients: dibasic calcium phosphate, FD&C Blue #1, FD&C Red #40, starch, stearic acid, and talc. Bottles of 100 and 1 000.
100 µg: Each round, yellow, scored tablet, engraved with 100 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 100 µg. Nonmedicinal ingredients: dibasic calcium phosphate, FD&C Yellow #5, FD&C Yellow #6, starch, stearic acid, and talc. Bottles of 100 and 1 000.
112 µg: Each round, rose, scored tablet, engraved with 112 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 112 µg. Nonmedicinal ingredients: dibasic calcium phosphate, FD&C Red #40, starch, stearic acid, talc and titanium dioxide. Bottles of 100 and 1 000.
125 µg: Each round, brown, scored tablet, engraved with 125 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 125 µg. Nonmedicinal ingredients: dibasic calcium phosphate, FD&C Blue #1, FD&C Red #40, starch, stearic acid, and talc. Bottles of 100 and 1 000.
150 µg: Each round, blue, scored tablet, engraved with 150 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 150 µg. Nonmedicinal ingredients: dibasic calcium phosphate, FD&C Blue #1, starch, stearic acid, and talc. Bottles of 100 and 1 000.
175 µg: Each round, lilac, scored tablet, engraved with 175 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 175 µg. Nonmedicinal ingredients: dibasic calcium phosphate, FD&C Blue #1, FD&C Red #40, starch, stearic acid, and talc. Bottles of 100 and 1 000.
200 µg: Each round, pink, scored tablet, engraved with 200 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 200 µg. Nonmedicinal ingredients: dibasic calcium phosphate, FD&C Red #3, starch, stearic acid, and talc. Bottles of 100 and 1 000.
300 µg: Each round, green, scored tablet, engraved with 300 and “M” on one side, and blank on the other side, contains: levothyroxine sodium USP 300 µg. Nonmedicinal ingredients: D&C Yellow #10, dibasic calcium phosphate, FD&C Blue #1, FD&C Yellow #6, starch, stearic acid, and talc. Bottles of 100 and 1 000.
Store between 15 and 30°C. Protect from light.
LEVOTEC Technilab Levothyroxine Sodium Hypothyroidism Therapy
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