001645 Liothyronine Sodium

DESCRIPTION

Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T4, levothyroxine) sodium or triiodothyronine (T3, liothyronine) sodium or both. T4 and T3 are produced in the human thyroid gland by the iodination and coupling of the amino acid tyrosine. T4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T3 contains three atoms of iodine and is formed by the coupling of one molecule of DIT with one molecule of monoiodotyrosine (MIT). Both hormones are stored in the thyroid colloid as thyroglobulin.

Thyroid Hormone Preparations Belong To Two Categories:

Tablets:

The empirical formula of liothyronine sodium is C15H11I3NNaO4. The molecular weight is 672.96.

L-Tyrosine, O -(4-hydroxy-3-iodophenyl) -3,5 -diiodo, monosodium salt

Twenty-five mcg of liothyronine is equivalent to approximately 1 grain of desiccated thyroid or thyroglobulin and 0.1 mg of L-thyroxine.

Each round, white to off-white Cytomel (liothyronine sodium) tablet contains liothyronine sodium equivalent to liothyronine as follows: 5 mcg debossed SKF and D14; 25 mcg scored and debossed. SKF and D16:50 mcg scored and debossed SKF and D17. Inactive ingredients consist of calcium sulfate, gelatin, starch, stearic acid, sucrose and talc.

Injection:

Triostat (liothyronine sodium injection) (T3) contains liothyronine (L-tri-iodothyronine or L-T3) a synthetic form of a natural thyroid hormone, as the sodium salt.

In euthyroid patients, 25 mcg of liothyronine is equivalent to approximately 1 grain of desiccated thyroid or thyroglobulin and 0.1 mg of L-thyroxine.

Each ml of Triostat in amber-glass vials contains, in sterile non- pyrogenic aqueous solution, sodium liothyronine equivalent to 10 mcg of liothyronine; alcohol, 6.8% by volume; anhydrous citric acid, 0.175 mg; ammonia, 2.19 mg as ammonium hydroxide.

CLINICAL PHARMACOLOGY

Tablets:

Injection:

While the source of levothyroxine (T4) and some triiodothyronine (T3) is via secretion from the thyroid gland, it is now well- established that approximately 80% of circulating T3 arises predominantly by way of the extrathyroidal conversion of T4. The membrane-bound enzyme responsible for this reaction is iodothyronine 5'- deiodinase. Activity of the enzyme is greatest in the liver and kidney. A second pathway to T4 to T3 conversion occurs via a PTU- insensitive 5'-deiodinase located primarily in the pituitary and central nervous system.

The prohormone T4 must be converted to T3 in the body before it can exert biological effects. During periods of illness or stress, this conversion is often inhibited and can be diverted to the inactive reverse T3 (rT3) moiety. Therefore, correction of the hypothyroid condition in patients with myxedema coma is facilitated by the parenteral administration of triiodothyronine (T3). T3 is bound much less firmly to serum binding proteins and therefore penetrates into the cells much more rapidly than T4. Also, the binding of T3 to a nuclear thyroid hormone in tissues. Although most thyroid hormone analogs, both natural and synthetic, will bind to this protein, the affinity of T3 for this receptor is roughly 10-fold higher than that of T4. Thus T3 is the biologically active thyroid hormone.

Pharmacodynamics

Injection:

Pharmacokinetics

Since liothyronine sodium (T3) is not firmly bound to serum protein, it is readily available to body tissues. The onset of activity of liothyronine sodium is rapid, occurring within a few hours. Maximum pharmacologic response occurs within two or three days, providing early clinical response. The biological half-life is about 2 1/2 days.

T3 is almost totally absorbed, 95 percent in four hours. The hormones contained in the natural preparations are absorbed in a manner similar to the synthetic hormones.

Liothyronine sodium has a rapid cutoff of activity which permits quick dosage adjustment and facilitates control of the effects of overdosage, should they occur.

The higher affinity of levothyroxine (T4) for both thyroid-binding globulin and thyroid-binding prealbumin as compared to triiodothyronine (T3) partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity.

Injection:

INDICATIONS AND USAGE

Tablets:

1.

As replacement of supplemental therapy in patients with hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. This category includes cretinism, myxedema and ordinary hypothyroidism in patients of any age (children, adults, the elderly), or state (including pregnancy); primary hypothyroidism resulting from functional deficiency, primary atrophy, partial or total absence of thyroid gland, or the effects of surgery, radiation, or drugs, with or without the presence of goiter; and secondary (pituitary) or tertiary (hypothalamic) hypothyroidism (See WARNINGS.)

2.

As pituitary thyroid-stimulating hormone (TSH) suppressants, in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto's) and multinodular goiter.

3.

As diagnostic agents in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy.

Cytomel (liothyronine sodium) Tablets can be used in patients allergic to desiccated thyroid or thyroid extract derived from pork or beef.

Injection:

Triostat can be used in patients allergic to desiccated thyroid or thyroid extract derived from pork or beef.

CONTRAINDICATIONS

Thyroid hormone preparations are generally contraindicated in patients with diagnosed but as yet uncorrected adrenal cortical insufficiency, untreated thyrotoxicosis and apparent hypersensitivity to any of their active or extraneous constituents. There is no well-documented evidence from the literature, however, of true allergic or idiosyncratic reactions to thyroid hormone.

WARNINGS

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.

The use of thyroid hormones in the therapy of obesity, alone or combined with other drugs, is unjustified and has been shown to be ineffective. Neither is their use justified for the treatment of male or female infertility unless this condition is accompanied by hypothyroidism.

Thyroid hormones should be used with great caution in a number of circumstances where the integrity of the cardiovascular system, particularly the coronary arteries, is suspected. These include patients with angina pectoris or the elderly, in whom there is a greater likelihood of occult cardiac disease. In these patients, liothyronine sodium therapy should be initiated with low doses, with due consideration for its relatively rapid onset of action.

Morphologic hypogonadism and nephrosis should be ruled out before the drug is administered. If hypopituitarism is present, the adrenal deficiency must be corrected prior to starting the drug.

Myxedematous patients are very sensitive to thyroid; dosage should be started at a very low level and increased gradually as acute changes may precipitate adverse cardiovascular events.

Severe and prolonged hypothyroidism can lead to a decreased level of adrenocortical activity commensurate with the lowered metabolic state. When thyroid-replacement therapy is administered, the metabolism increases at a greater rate than adrenocortical activity. This can precipitate adrenocortical insufficiency. Therefore, in severe and prolonged hypothyroidism, supplemental adrenocortical steroids may be necessary.

In rare instances the administration of thyroid hormone may precipitate a hyperthyroid state or may aggravate existing hyperthyroidism.

Tablets:

Injection:

Extreme caution is advised when administering thyroid hormones with digitalis or vasopressors. (See DRUG INTERACTIONS.)

Fluid therapy should be administered with great care to prevent cardiac decompensation. (See PRECAUTIONS, Adjunctive Therapy.)

PRECAUTIONS

General

Thyroid hormone therapy in patients with concomitant diabetes mellitus (see DRUG INTERACTIONS, Insulin or Oral Hypoglycemics regarding interaction and dose adjustment with insulin) or insipidus or adrenal cortical insufficiency aggravates the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases are required.

The therapy of myxedema coma requires simultaneous administration of glucocorticoids. (See PRECAUTIONS, Adjunctive Therapy.)

Hypothyroidism decreases and hyperthyroidism increases 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.

Injection

General:

Adjunctive Therapy:

In considering the need to elevate blood pressure, it should be kept in mind that tissue metabolic requirements are markedly reduced in the hypothyroid patient. Because arrhythmias and circulatory collapse have infrequently occurred following the concomitant administration of thyroid hormones and vasopressor therapies, use caution when administering these therapies consistently (see DRUG INTERACTIONS, Vasopressors) .

Hyponatremia is frequently present in myxedema coma, but usually resolves without specific therapy as the metabolic status of the patient is improved with thyroid hormone treatment. Fluid therapy should be administered with great care to prevent cardiac decompensation. In addition, some patients with myxedema have inappropriate secretion of ADH and are susceptible to water intoxication.

In some patients, respiratory depression has been a significant factor in the development or the persistence of the comatose state. Decreased oxygen saturation and elevated C02 levels respond quickly to artificial respiration.

Infection is often present in myxedema coma and should be looked for and treated appropriately.

Concomitant use of Triostat and artificial rewarming of patients is contraindicated. Although patients in myxedema coma are often hypothermic, most investigators believe that the artificial warming is of little value or may be harmful. The peripheral vasodilation produced by external heat serves to further decrease circulation to vital internal organs and to increase shock if present. It has been reported that the administration of liothyronine sodium will restore a normal body temperature in 24 to 48 hours if heat loss is prevented by keeping the patient covered with blankets in a warm room.

Drug/Laboratory Test Interactions

The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroid hormone therapy: androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-containing preparations and the numerous preparations containing salicylates.

Tablets

1.

Changes in TBG concentration should be taken into consideration in the interpretation of T4 and T3 values. In such cases, the unbound (free) hormone should be measured. Pregnancy, estrogens and estrogen- containing oral contraceptives increase TBG concentrations. TBG may also be increased during 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 approximates 1 in 9000. The binding of thyroxine by thyroxine-binding prealbumin (TBPA) is inhibited by salicylates.

2.

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

3.

The persistence of clinical and laboratory evidence of hypothyroidism in spite of adequate dosage replacement indicates either poor patient compliance, poor absorption, excessive fecal loss, or inactivity of the preparation. Intracellular resistance to thyroid hormone is quite rare.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A reportedly apparent association between prolonged thyroid therapy and breast cancer has not been confirmed and patients on thyroid for established indications should not discontinue therapy. No confirmatory long-term studies in animals have been performed to evaluate carcinogenic potential, mutagenicity, or impairment of fertility in either males or females.

Pregnancy Category A

Thyroid hormones do not readily cross the placental barrier. The 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, thyroid replacement therapy to hypothyroid women should not be discontinued during pregnancy.

Nursing Mothers

Minimal amounts of thyroid hormones are excreted in human milk. Thyroid is not associated with serious adverse reactions and does not have a known tumorigenic potential. However, caution should be exercised when thyroid is administered to a nursing woman.

Tablets:

Information for the Patient

Patients on thyroid hormone preparations and parents of children on thyroid therapy 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.

They should immediately report during the course of therapy 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 thyroid medication is stopped, a downward readjustment of the dosage of insulin or oral hypoglycemic agent may be necessary to avoid hypoglycemia. At all times, close monitoring of urinary glucose levels is mandatory in such patients.

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.

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 usually the rule.

Laboratory Tests

Treatment of patients with thyroid hormones requires the periodic assessment of thyroid status by means of appropriate laboratory tests besides the full clinical evaluation. The TSH suppression test can be used to test the effectiveness of any thyroid preparation, bearing in mind the relative insensitivity of the infant pituitary to the negative feedback effect of thyroid hormones. Serum T4 levels can be used to test the effectiveness of all thyroid medications except products containing liothyronine sodium. When the total serum T4 is low but TSH is normal, a test specific to assess unbound (free) T4 levels is warranted. Specific measurements of T4 and T3 by competitive protein binding or radioimmunoassay are not influenced by blood levels of organic or inorganic iodine and have essentially replaced older tests of thyroid hormone measurements, i.e. , PBI, BEI and T4 by column.

Injection:

Pediatric Use

Pregnant mothers provide little or no thyroid hormone to the fetus. The incidence of congenital hypothyroidism is relatively high (1:4000) and the hypothyroid fetus would not derive any benefit from the small amounts of hormone crossing the placental barrier. Routine determinations of serum T4 and/or TSH is strongly advised in neonates in view of the deleterious effects of thyroid deficiency on growth and development.

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.

Injections:

DRUG INTERACTIONS

Oral Anticoagulants:

Insulin or Oral Hypoglycemics:

Estrogen, Oral Contraceptives:

Tricyclic Antidepressants:

Digitalis:

Ketamine:

Vasopressors:

Tablets

Cholestyramine:

ADVERSE REACTIONS

Tablets:

In rare instances, allergic skin reactions have been reported with Cytomel (liothyronine sodium) Tablets.

Injection:

In rare instances, allergic skin reactions have been reported with liothyronine sodium tablets.

OVERDOSAGE

Signs and Symptoms

Headache, irritability, nervousness, sweating, tachycardia, increased bowel motility and menstrual irregularities. Angina pectoris or congestive heart failure may be induced or aggravated. Shock may also develop if there is untreated pituitary or adrenocortical failure. Massive overdosage may result in symptoms resembling thyroid storm. Chronic excessive dosage will produce the signs and symptoms of hyperthyroidism.

Treatment

Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis function is restored in six to eight weeks after thyroid suppression.

Tablets

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 and barring contraindications such as coma, convulsions, or loss of the gagging reflex. Treatment is 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 pf over a 10-minute period or orally, 80 to 160 mg/day, especially when no contraindications exist for its use.

Injection

Treatment is symptomatic and supportive. Oxygen may be administered and ventialtion maintained. Cardiac glycosides may be indicated if congestive heart failure develops. Beta-adrenergic antagonists have been used advantageously in the treatment of increased sympathetic activity. Measures to control fever, hypoglycemia or fluid loss should be instituted if needed.

DOSAGE AND ADMINISTRATION

Tablets:

Cytomel (liothyronine sodium) Tablets are intended for oral administration; once-a-day dosage is recommended. Although liothyronine sodium has a rapid cutoff, its metabolic effects persist for a few days following discontinuance.

Mild Hypothyroidism:

The rapid onset and dissipation of action of liothyronine sodium (T3), as compared with levothyroxine sodium (T4), has led some clinicians to prefer its use in patients who might be more susceptible to the untoward effects of thyroid medication. However, the wide swings in serum T3 levels that follow its administration and the possibility of more pronounced cardiovascular side effects tend to counterbalance the stated advantages.

Cytomel (liothyronine sodium) Tablets may be used in preference to levothyroxine (T4) during radioisotope scanning procedures, since induction of hypothyroidism in those cases is more abrupt and can be of shorter duration. It may also be preferred when impairment of peripheral conversion of T4 and T3 is suspected.

Myxedema:

Myxedema Coma:

Congenital Hypothyroidism:

Simple (non-toxic) Goiter:

In the elderly or in children

When switching a patient to Cytomel (liothyronine sodium) Tablets

Thyroid Suppression Therapy:

Cytomel (liothyronine sodium) Tablets are given in doses of 75 to 100 mcg/day for 7 days, and radioactive iodine uptake is determined before and after administration of the hormone. If thyroid function is under normal control, the radioiodine uptake will drop significantly after treatment. Cytomel (liothyronine sodium) Tablets should be administered cautiously to patients in whom there is a strong suspicion of thyroid gland autonomy, in view of the fact that the exogenous hormone effects will be additive to the endogenous source.

Injection:

Adults:

Triostat (liothyronine sodium injection (T3) is for intravenous administration only. It should not be given intramuscularly or subcutaneously.

Prompt administration of an adequate dose of intravenous liothyronine (T3) is important in determining clinical outcome.

Initial and subsequent doses of Triostat should be based on continuous monitoring of the patient's clinical status and response to therapy.

Triostat doses should normally be administered at least four hours- and not more than 12 hours-apart.

Administration of at least 65 mcg/day of intravenous liothyronine (T3) in the initial days of therapy was associated with lower mortality.

There is limited clinical experience with intravenous liothyronine.

(T3) at total daily doses exceeding 100 mcg/day.

No controlled clinical studies have been done with Triostat. The following dosing guidleines have been derived from data analysis of myxedema coma/precoma case reports collected by SmithKline Beecham Pharmaceuticals since 1963 and from scientific literature since 1956.

An initial intravenous Triostat dose ranging from 25 mcg to 50 mcg is recommended in the emergency treatment of myxedema coma/precoma in adults. In patients with known or suspected cardiovascular disease, an initial dose of 10 mcg to 20 mcg is suggested (see WARNINGS.) However, both the initial dose and subsequent doses should be determined on the basis of continuous monitoring of the patient's clinical condition and response to Triostat therapy. Normally at least four hours should be allowed between doses to adequately assess therapeutic response and no more than 12 hours should elapse between doses to avoid fluctuation in hormone levels. Caution should be exercised in adjusting the dose due to the potential of large changes in precipitate adverse cardiovascular events. Review of the myxedema case reports indicate decreased mortality in patients receiving at least 65 mcg/day in the initial days of treatment. However, there is limited clinical experience at total daily doses above 100 mcg. See DRUG INTERACTIONS for potential interactions between thyroid hormones and digitalis and vasopressors.

Pediatric Use:

Switching to Oral Therapy:

If L-thyroxine rather than liothyronine sodium is used in initiating oral therapy, the physician should bear in mind that there is a delay of several days in the onset of L-thyroxine activity and that intravenous therapy should be discontinued gradually.

HOW SUPPLIED

Tablet:

Injection:

Store between 2 and 8°C.