Thyrolar

DESCRIPTION

Thyrolar Tablets (Liotrix Tablets, USP) containtriiodothyronine(T₃liothyronine) sodium and tetraiodothyronine (T₄levothyroxine) sodium in the amounts listed in the "How Supplied" section. (T₃liothyronine sodium is approximately four times as potent as T₄thyroxineon a microgram for microgram basis.)

The inactive ingredients are calcium phosphate, colloidalsilicondioxide, corn starch, lactose, and magnesium stearate. The tablets also contain the following dyes: Thyrolar (liotrix) 1/4 - FD&C Blue #1 and FD&C Red #40; Thyrolar (liotrix) ½ - FD&C Red #40 and D&C Yellow #10; Thyrolar (liotrix) 1 - FD&C Red #40; Thyrolar (liotrix) 2 - FD&C Blue #1, FD&C Red #40, and D&C Yellow #10; Thyrolar (liotrix) 3 - FD&C Red #40 and D&C Yellow #10.

STRUCTURAL FORMULAS

INDICATIONS

Thyrolar (liotrix) Tablets are indicated:

1. 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警告）.
2. As pituitary TSH suppressants, in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic Iymphocytic thyroiditis (Hashimoto's), multinodular goiter, and in the management of thyroid cancer.
3. As diagnostic agents in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy.

DOSAGE AND ADMINISTRATION

The dosage of Thyrolar Tablets (Liotrix Tablets, USP) 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. Intramuscular administration 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 one tablet of Thyrolar (liotrix) ½ with increments of one tablet of Thyrolar (liotrix) !4 every 2 to 3 weeks. A lower starting dosage, one tablet of Thyrolar (liotrix) %/day, is recommended in patients with long-standing 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. Most patients require one tablet of Thyrolar (liotrix) 1 to one tablet of Thyrolar (liotrix) 2 per day. Failure to respond to doses of one tablet of Thyrolar (liotrix) 3 suggests lack of compliance or malabsorption. Maintenance dosages of one tablet of Thyrolar (liotrix) 1 to one tablet of Thyrolar (liotrix) 2 per day usually result in normal serum levothyroxine (T₄) and triiodothyronine (T₃) levels. Adequate therapy usually results in normal TSH and T₄levels 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.

T₃may be used in preference to levothyroxine (T₄) during radio-isotope 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 T₄and T₃is 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. T₄and T₃may 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 T₄levels are achieved in 24 hours followed in 3 days by threefold elevation of T₃. Oral therapy with thyroid 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

政府高剂量的甲状腺激素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 Grave's ophthalmopathy. 131I 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 1.56 mcg/kg of body weight per day given for 7 to 10 days. These doses usually yield normal serum T₄and T₃levels and lack of response to TSH.

Thyroid hormones should be administered cautiously to patients in whom there is 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.

Recommended Pediatric Dosage for Congenital Hypothyroidism

	Dose per day in mcg
Age	T3/T4to T3/T4
0-6 mos	3.1/12.5 to 6.25/25
6-12 MOs	6.25/25 to 9.35/37.5
1-5 yrs	9.35/37.5 to 12.5/50
6-12 yrs	12.5/50 to 18.75/75
Over 12 yrs	over 18.75/75

HOW SUPPLIED

Thyrolar Tablets (Liotrix Tablets, USP) are available in five potencies coded as follows:

Name	Composition (T3/T4per tablet)	Color	Armacode®	NDC
Thyrolar-1/4	3.1 mcg/ 12.5 mcg	Violet/White	YC	0456-0040-01
Thyrolar-½	6.25 mcg/ 25 mcg	Peach/White	YD	0456-0045-01
Thyrolar-1	12.5 mcg/ 50 mcg	Pink/White	YE	0456-0050-01
Thyrolar-2	25 mcg/ 100 mcg	Green/White	YF	0456-0055-01
Thyrolar-3	37.5毫克/ 150微克	Yellow/White	YH	0456-0060-01

Supplied in bottles of 100, two-layered compressed tablets.

平板电脑应该存储在寒冷的温度下,元素een 36F and 46F (2C and 8C) in a tight, light-resistant container.

Note: (T₃liothyronine sodium is approximately four times as potent as T₄thyroxine on a microgram for microgram basis.)

Forest Pharmaceuticals, Inc. A Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045. Rev. 04/05

SIDE EFFECTS

During postmarketing surveillance, the following events have been observed to have occured in patients administered Thyrolar (liotrix) : fatigue, sluggishness, increase in weight, alopecia, palpitations, dry skin, urticaria, headache, hyperhidrosis, pruritus, asthenia, increased blood pressure, arthralgia, myalgia, tremor, hypothyroidism, increase in TSH, decrease in TSH, nausea, chest pain, hypersensitivity, keratoconjunctivitis sicca, increased heart rate, irregular heart rate, anxiety, depression, and insomnia.

Adverse reactions other than those indicative of hyperthyroidism because of therapeutic overdosage, either initially or during the maintenance period, are rare (SeeOVERDOSAGE）.

DRUG INTERACTIONS

Oral Anticoagulants

甲状腺激素增加分解代谢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 dose 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 or Colestipol

Cholestyramine or colestipol binds both T₄and T₃in the intestine thus impairing absorption of these thyroid hormones.In vitrostudies indicate that the binding is not easily removed. Therefore, four to five hours should elapse between administration of cholestyramine or colestipol andthyroid hormones.

Estrogen, Oral Contraceptives

Estrogenstend to increase serum thyroxine-binding globulin (TBg). In a patient with a nonfunctioningthyroid glandwho is receivingthyroidreplacement therapy, free levothyroxine may be decreased when estrogens are started, thus increasing thyroid requirements. However, if the patient's thyroidglandhas 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 orestrogen-containing oral contraceptives are given.

Drug/Laboratory Test Interactions

The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroidhormone 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 T₄and T₃values. 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 duringinfectious hepatitis. Decreases in TBg concentrations are observed innephrosis,acromegaly, and afterandrogenorcorticosteroidtherapy.Familialhyper- or hypothyroxine-binding-globulinemias have been described. The incidence of TBg deficiency approximates 1 in 9,000. The binding of thyroxine by TBPA is inhibited by salicylates.
2. 药用或食用碘干扰in vivotests of radio-iodine uptake, producing low uptakes which may not be relative of a true decrease in hormone synthesis.
3. The persistence of clinical and laboratory evidence ofhypothyroidismin spite of adequate dosage replacement indicates either poor patient compliance, poor absorption, excessive fecal loss, or inactivity of the preparation. Intracellular resistance tothyroid hormoneis quite rare.

警告

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 femaleinfertilityunless this condition is accompanied by hypothyroidism.

PRECAUTIONS

General

Thyroid hormones should be used with great caution in a number of circumstances where the integrity of thecardiovascular system, particularly the coronary arteries, is suspected. These include patients withangina pectorisor the elderly, in whom there is a greater likelihood ofoccultcardiac disease. In these patients therapy should be initiated with low doses, i.e., one tablet of Thyrolar (liotrix) % or Thyrolar (liotrix) %. When, in such patients, a euthyroid state can only be reached at the expense of an aggravation of thecardiovascular disease, thyroid hormone dosage should be reduced.

Thyroid hormone therapy in patients with concomitantdiabetes mellitusordiabetes insipidusor adrenalcorticalinsufficiency aggravates the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases are required. The therapy ofmyxedema comarequires simultaneous administration of glucocorticoids (SeeDOSAGE AND ADMINISTRATION）.

Hypothyroidism decreases and hyperthyroidism increases the sensitivity to oral anticoagulants.Prothrombin timeshould be closely monitored in thyroid treated patients on oral anticoagulants and dosage of the latter agents adjusted on the basis of frequentprothrombintime determinations. In infants, excessive doses of thyroid hormone preparations may producecraniosynostosis.

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 infantpituitaryto the negative feedback effect of thyroid hormones. Serum T₄levels can be used to test the effectiveness of all thyroid medications except T₃. When the total serum T₄is low but TSH is normal, a test specific to assess unbound (free) T₄levels is warranted. Specific measurements of T₄and T₃by competitive protein binding orradioimmunoassayare not influenced by blood levels of organic or inorganic iodine.

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 evaluatecarcinogenicpotential, 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 anyadverse effecton 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 ofcongenital hypothyroidismis 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.

OVERDOSE

Signs and Symptoms

Excessive doses of thyroid result in a hypermetabolic state resembling in every respect the condition ofendogenousorigin. The condition may be self-induced.

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. In normal individuals, normal hypothalamic-pituitary-thyroidaxisfunction is restored in 6 to 8 weeks after thyroid suppression.

Treatment of acute massive thyroid hormone overdosage is aimed at reducinggastrointestinalabsorption 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 andventilationmaintained. Cardiac glycosides may be indicated ifcongestive heart failuredevelops. 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.

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.

CLINICAL PHARMACOLOGY

The steps in the synthesis of the thyroid hormones are controlled bythyrotropin(Thyroid Stimulating Hormone, TSH) secreted by theanterior 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), atripeptideof hypothalamic origin. Endogenous thyroid hormone secretion is suppressed whenexogenousthyroid hormones are administered to euthyroid individuals in excess of the normal gland's secretion.

The mechanisms by which thyroid hormones exert theirphysiologicaction are not well understood. These hormones enhance oxygen consumption by most tissues of the body, increase thebasal metabolic rate, and themetabolismofcarbohydrates,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 thecentral nervous system.

The normal thyroid gland contains approximately 200 mcg of levothyroxine (T₄) pergramof gland, and 15 mcg of triiodothyronine (T₃) per gram. The ratio of these two hormones in thecirculationdoes not represent the ratio in the thyroid gland, since about 80 percent of peripheral triiodothyronine comes from mon-odeiodination of levothyroxine. Peripheral monodeiodination of levothyroxine at the 5 position (inner ring) also results in the formation of reverse triiodothyronine (T₃), which is calorigenically inactive.

Triiodothyronine (T₃) levels are low in the fetus and newborn, in old age, in chronic caloric deprivation, hepaticcirrhosis, renal failure, surgicalstress, and chronic illnesses representing what has been called the "low triiodothyronine syndrome."

Pharmacokinetics

Animal studies have shown that T₄is 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 intestinalflora, 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 agelatincapsule as opposed to a 74 percent absorption when given with analbumincarrier.

Depending on other factors, absorption has varied from 48 to 79 percent of the administered dose. Fasting increases absorption.Malabsorptionsyndromes, as well as dietary factors (children's soybean formula, concomitant use of anionic exchange resins such as cholestyramine) cause excessive fecal loss. T₃is 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-bindingprealbumin(TBPA), and albumin (TBa), whose capacities and affinities vary for the hormones. The higheraffinityof 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 thebileand gut where it may complete an enterohepatic circulation. Eighty-five percent of levothyroxine (T₄) metabolized daily is deiodinated.

PATIENT INFORMATION

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 withthyroiditis, 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, increasedpulserate,palpitations过度出汗,heat intolerance, nervousness, or any other unusual event.
3. In case of concomitantdiabetesmellitus, 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 ofinsulinor oralhypoglycemicagent 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 oralanticoagulanttherapy, 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.
6. 平板电脑应该存储在寒冷的温度下,元素een 36°F and 46°F (2°C and 8°C) in a tight, light-resistant container.