001646 Liotrix (T3 and T4)
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001646 Liotrix (T3 and T4) |
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CATEGORIES: HypothyroidismMyxedemaPregnancy Category AFDA Approval Pre 1982 FDS Drug Classes: Hormones/hormone modifiersThyroid agents BRAND NAMES: Cynoplus 3 Euthroid Euthroid 2 Eutroid Proloid S-1 Proloid S-2 Thyreotom Thyreotom Forte Thyrolar FOREIGN BRAND AVAILABILITY: Cynoplus 3 (Mexico)Euthroid 2 (Colombia) Eutroid (Peru) Proloid S-1 (Mexico) Proloid S-2 (Mexico) Thyreotom (Cyprus; Egypt; Iraq; Jordan; Libya; Syria) Thyreotom Forte (Bahrain; Cyprus; Egypt; Iran; Iraq; Jordan; Kuwait; Lebanon; Libya; Oman; Qutar; Republic-of-Yemen; Saudi-Arabia; Syria; United-Arab-Emirates) |
Liotrix tablets, USP is synthetic microcrystalline levothyroxine sodium (T4) USP and synthetic microcrystalline liothyronine sodium (T3) USP combined in a constant 4:1 ratio. Each Liotrix-1 tablet contains 60 mcg levothyroxine (T4) and 15 mcg liothyronine (T3).
Each Liotrix-1 tablet will give a dose benefit approximately equivalent to 1 grain of desiccated thyroid, 100 mcg T4 (levothyroxine sodium), 25 mcg T3 (liothyronine sodium), or 60 mcg T4/15 mcg T3 (liotrix).
See Conversion Table at end of insert.
Liotrix tablets also contain calcium phosphate, USP; cellulose, NF; corn starch, NF; hydrogenated vegetable oil, NF; magnesium stearate, NF; mannitol, USP; and silicon dioxide, NF. In addition, Liotrix-1/2 contains D&C red No. 30 lake and FD&C yellow No. 5 lake. Liotrix-1 and Liotrix-3 contain D&C red No. 30 lake, FD&C blue No. 2 lake and FD&C yellow No. 5 lake. Liotrix-2 contains D&C red No. 30 lake and FD&C blue No. 2 lake.
Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T4, levothyroxine) sodium or triiodothyronine (T3, liothyronine) sodium or both. T4and 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: (1) natural hormonal preparations derived from animal thyroid, and (2) synthetic preparations. Natural preparations include desiccated thyroid and thyroglobulin. Desiccated thyroid is derived from domesticated animals that are used for food by man (either beef or hog thyroid), and thyroglobulin is derived from thyroid glands of the hog.
There are five (5) preparations in the USP. They are: (1) Thyroid Tablets, (21) Thyroglobulin Tablets, (3) Levothyroxine Sodium Tablets, (4) Liothyronine Sodium Tablets, and (5) Liotrix Tablets (a ratio, by weight, of 4 to 1, of the sodium salts of T4 and T3, respectively).
The empirical formulas, molecular weights, and Chemical Abstract Service (CAS) registry numbers of the synthetic sodium salts T4 and T3 are given below.
Liothyronine (T3) Sodium
C15H11I3NNaO4 MW 672.96 (CAS 55-06-1)
L-Tyrosine, O -(4-hydroxy -3-iodophenyl)-3,5 -diiodo-monosodium salt
Levothyroxine (T4) Sodium
C15H10I4NNaO4-xH2O (CAS 25416-65-3)
MW 798.86(anhydrous) (CAS 55-03-8)
L-Tyrosine, O -(4-hydroxy -3,5-diiodophenyl)-3,5-diiodo-monosodium salt, hydrate
The steps in the synthesis of the thyroid hormones are controlled by thyrotropin (Thyroid Stimulating Hormone, TSH) secreted by the anterior pituitary. This hormone's secretion is in turn controlled by a feedback mechanism effected by the thyroid hormones themselves and by thyrotropin releasing hormone (TRH), a tripeptide of hypothalamic origin. Endogenous thyroid hormone secretion is suppressed when exogenous thyroid hormones are administered to euthyroid individuals in excess of the normal gland's secretion.
The mechanisms by which thyroid hormones exert their physiologic action are not well understood. These hormones enhance oxygen consumption by most tissues of the body, increase the basal metabolic rate, and the metabolism of carbohydrates, lipids, and proteins. Thus, they exert a profound influence on every organ system in the body and are of particular importance in the development of the central nervous system.
The normal thyroid gland contains approximately 200 mcg of levothyroxine (T4) per gram of gland, and 15 mcg of triiodothyronine (T3) per gram. The ratio of these two hormones in the circulation does not represent the ratio in the thyroid gland, since about 80 percent of peripheral triiodothyronine comes from monodeiodination of levothyroxine. Peripheral monodeiodination of levothyroxine at the 5 position (inner ring) also results in the formation of reverse triiodothyronine (rT3), which is calorigenically inactive. These facts would seem to advocate levothyroxine as the treatment of choice for the hypothyroid patient and to militate against the administration of hormone combinations, which while normalizing thyroxine levels may produce triiodothyronine levels in the thyrotoxic range.
Triiodothyronine (T3) level is low in the fetus and newborn, in old age, in chronic caloric deprivation, hepatic cirrhosis, renal failure, surgical stress, and chronic illnesses representing what has been called the "low triiodothyronine syndrome."
Pharmacokinetics:
Animal studies have shown that T4 is only partially absorbed from the gastrointestinal tract. The degree of absorption is dependent on the vehicle used for its administration and by the character of the intestinal contents, the intestinal flora, including plasma protein, soluble dietary factors, all of which bind thyroid and thereby make it unavailable for diffusion. Only 41 percent is absorbed when given in a gelatin capsule as opposed to a 74 percent absorption when given with an albumin carrier.Depending on the other factors, absorption has varied from 48 to 79 percent of the administered dose. Fasting increases absorption. Malabsorption syndromes, as well as dietary factors (children's soybean formula, concomitant use of anionic exchange resins such as cholestyramine), cause excessive fecal loss. T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the natural preparations are absorbed in a manner similar to the synthetic hormones.
More than 99 percent of circulating hormones are bound to serum proteins, including thyroid-binding globulin (TBg), thyroid-binding prealbumin (TBPA), and albumin (TBa), whose capacities and affinities vary for the hormones. The higher affinity of levothyroxine (T4) for both TBg and TBPA 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.
Deiodination of levothyroxine (T4) occurs at a number of sites, including liver, kidney, and other tissues. The conjugated hormone, in the form of glucuronide or sulfate, is found in the bile and gut where it may complete an enterohepatic circulation. Eighty-five percent of levothyroxine (T4) metabolized daily is deiodinated.
Thyroid hormone drugs are indicated:
As replacement or 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.)
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.
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.
General:
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 suspect. These include patients with angina pectoris or the elderly, in whom there is a greater likelihood of occult cardiac disease. In these patients, therapy should be initiated with low doses, i.e., 25-50 mcg levothyroxine (T4) or its isocaloric equivalents (see Conversion Table at end of insert) . When, in such patients, a euthyroid state can only be reached at the expense of an aggravation of the cardiovascular disease, thyroid hormone dosage should be reduced.Thyroid hormone therapy in patients with concomitant diabetes mellitus 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 DOSAGE AND ADMINISTRATION.)
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 determination. In infants, excessive doses of thyroid hormone preparations may produce craniosynostosis.
Liotrix-1/2, -1, -3 contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
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 T3. When the total serum T4 is low but TSH is normal, a test specific to assess unbound (free) T4levels 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.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.1.
Changes in TBg concentration should be taken into consideration in the interpretation of T4 and T3 values. In such cases, the unbound (free) hormones 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 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 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.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 are 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.
Oral Anticoagulants:
Thyroid hormones appear to increase catabolism of vitamin-K-dependent clotting factors. If oral anticoagulants are also being given, compensatory increases in clotting factor synthesis are impaired. Patients stabilized on oral anticoagulants who are found to require thyroid replacement therapy should be watched very closely when thyroid is started. If a patient is truly hypothyroid, it is likely that a reduction in anticoagulant dosage will be required. No special precautions appear to be necessary when oral anticoagulant therapy is begun in a patient already stabilized on maintenance thyroid replacement therapy.Insulin or Oral Hypoglycemics:
Initiating thyroid replacement therapy may cause increases in insulin or oral hypoglycemic requirements. The effects seen are poorly understood and depend upon a variety of factors such as dosage and type of thyroid preparations and endocrine status of the patient. Patients receiving insulin or oral hypoglycemics should be closely watched during initiation of thyroid replacement therapy.Cholestyramine:
Cholestyramine binds both T4 and T3 in the intestine, thus impairing absorption of these thyroid hormones. In vitro studies indicate that the binding is not easily removed. Therefore, four to five hours should elapse between administration of cholestyramine or similar resins, such as colestipol, and thyroid hormones.Estrogen, Oral Contraceptives:
Estrogens tend to increase serum thyroxine-binding globulin (TBg). In a patient with a nonfunctioning thyroid gland who is receiving thyroid replacement therapy, free levothyroxine may be decreased when estrogens are started, thus increasing thyroid requirements. However, if the patient's thyroid gland has sufficient function, the decreased free thyroxine will result in a compensatory increase in thyroxine output by the thyroid. Therefore, patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their thyroid dose if estrogens or estrogen-containing oral contraceptives are given.Adverse reactions other than those indicative of hyperthyroidism because of therapeutic overdosage, either initially or during the maintenance period, are rare (see OVERDOSAGE.)
Signs and Symptoms:
Excessive doses of thyroid result in a hypermetabolic state resembling in every respect the condition of endogenous origin. The condition may be self-induced.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 6 to 8 weeks after thyroid suppression.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 mg over a 10 minute period or orally, 80 to 160 mg/day initially, especially when no contraindications exist for its use.
The dosage of thyroid hormones is determined by the indication and must in every case be individualized according to patient response and laboratory findings.
Thyroid hormones are given orally. In acute, emergency conditions, injectable sodium levothyroxine may be given intravenously when oral administration is not feasible or desirable, as in the treatment of myxedema coma, or during total parenteral nutrition. Injectable sodium liothyronine is also available upon request from the manufacture, under investigational status, for the treatment of myxedema coma. Intramuscular administration of these two preparations is not advisable because of reported poor absorption.
Hypothyroidism:
Therapy is usually instituted using low doses, with increments which depend on the cardiovascular status of the patient. The usual starting dose is 50 mcg of levothyroxine (T4) or its isocaloric equivalent (Liotrix-1/2), with increments of 25 mcg every 2 to 3 weeks. A lower starting dosage, 25 mcg/day of levothyroxine (T4) or its isocaloric equivalent, is recommended in patients with longstanding myxedema, particularly if cardiovascular impairment is suspected, in which case extreme caution is recommended. The appearance of angina is an indication for a reduction in dosage. The 200 to 400 mcg levothyroxine (T4) recommended in the early trials are now considered excessive and most patients require 100 to 200 mcg/day or the caloric equivalent. Failure to respond to doses of 300 mcg suggests lack of compliance or malabsorption. Maintenance dosages of 100-200 mcg/day (Liortrix-1 or Liotrix-2) usually result in normal serum levothyroxine (T4) and triiodothyronine (T3) levels. Adequate therapy usually results in normal TSH and T4 levels after 2 to 3 weeks of therapy.Readjustment of thyroid hormone dosage should be made within the first four weeks of therapy, after proper clinical and laboratory evaluations, including serum levels of T4, bound and free, and TSH.
The rapid onset and dissipation of action of sodium liothyronine (T3), as compared with sodium levothyroxine (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. Many physicians continue to use thyroid tablets, USP, a T3/T4 combination, or a newer synthetic combination.
T3 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 Coma:
Myxedema coma is usually precipitated in the hypothyroid patient of long standing by intercurrent illness or drugs such as sedatives and anesthetics and should be considered a medical emergency. Therapy should be directed at the correction of electrolyte disturbances and possible infection besides the administration of thyroid hormones. Corticosteroids should be administered routinely. T4 and T3 may be administered via a nasogastric tube, but the preferred route of administration of both hormones is intravenous. Sodium levothyroxine (T4) is given at a starting dose of 400 mcg (100 mcg/ml) given rapidly and is usually well tolerated, even in the elderly. This initial dose is followed by daily supplements of 100 to 200 mcg given IV. Normal T4 levels are achieved in 24 hours followed in 3 days by threefold elevation of T3. Triiodothyronine (T3) (which is obtained only by special request from the manufacturer) is given at doses of 200 mcg IV followed by 25 mcg supplements at 8-hour intervals. Oral therapy with either hormone would be resumed as soon as the clinical situation has been stabilized and the patient is able to take oral medication.Thyroid Cancer:
Exogenous thyroid hormone may produce regression of metastases from follicular and papillary carcinoma of the thyroid and is used as ancillary therapy of these conditions with radioactive iodine. TSH should be suppressed to low or undetectable levels. Therefore, larger amounts of thyroid hormone than those used for replacement therapy are required. Medullary carcinoma of the thyroid is usually unresponsive to this therapy.Thyroid Suppression Therapy:
Administration of thyroid hormone in doses higher than those produced physiologically by the gland results in suppression of the production of endogenous hormone. This is the basis for the thyroid suppression test and is used as an aid in the diagnosis of patients with signs of mild hyperthyroidism in whom baseline laboratory tests appear normal or to demonstrate thyroid gland autonomy in patients with Graves' ophthalmopathy. Radioiodine uptake is determined before and after the administration of the exogenous hormone. A fifty percent or greater suppression of uptake indicates a normal thyroid-pituitary axis and thus rules out thyroid gland autonomy.For adults, the usual suppressive dose of levothyroxine (T4) is 2.6 mcg/kg of body weight per day given for 7 to 10 days. These doses usually yield normal serum T4 and T3 levels and lack of response to TSH.
T3 is given in doses of 75-100 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 with either hormone.
Either hormone or combination therapy 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.
Pediatric Dosage:
Pediatric dosage should follow the recommendations summarized in TABLE 1. In infants with congenital hypothyroidism, therapy with full doses should be instituted as soon as the diagnosis has been made.| Tetraiodothyronine (T4, levothyroxine) sodium | ||
| Age | Dose per day | Daily dose per kg of body weight |
| 0-6 mos | 25-50 mcg | 8-10 mcg |
| 6-12 mos | 50-75 mcg | 6-8 mcg |
| 1-5 yrs | 75-100 mcg | 5-6 mcg |
| 6-12 yrs | 100-150 mcg | 4-5 mcg |
| over 12 yrs | over 150 mcg | 2-3 mcg |
| (Liotrix tablets, USP) | Natural | Synthetic | |||
| Tablet | T4*/T3** mcg | Color | Thyroid USP | T4* | T3** |
| Liotrix -1/2 | (30/7.5) | pale orange | 1/2 grain | 0.05 mg | 12.5 mcg |
| Liotrix -1 | (60/15) | light brown | 1 grain | 0.1 mg | 25.0 mcg |
| Liotrix -2 | (120/30) | violet | 2 grains | 0.2 mg | 50.0 mcg |
| Liotrix -3 | (180/45) | gray | 3 grains | 0.3 mg | 75.0 mcg |
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* T4 =levothyroxine sodium (l-thyroxine) | |||||
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** T3 = liothyronine sodium (l -triiodothyronine) | |||||
Following a change from one type of thyroid hormone preparation to another, patients may still require fine adjustment of dosage because the equivalents are only estimates.
Store between 15° and 25°C (59 and 77°F).