LIOTHYRONINE: 2,747 Adverse Event Reports & Safety Profile

DESCRIPTION Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T 4 , levothyroxine) sodium or triiodothyronine (T 3 , liothyronine) sodium or both. T 4 and T 3 are produced in the human thyroid gland by the iodination and coupling of the amino acid tyrosine. T 4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T 3 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 and released into the circulation. The major source of T 3 has been shown to be peripheral deiodination of T 4 . T 3 is bound less firmly than T 4 in the serum, enters peripheral tissues more readily, and binds to specific nuclear receptor(s) to initiate hormonal, metabolic effects. T 4 is the prohormone which is deiodinated to T 3 for hormone activity. 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. Liothyronine sodium injection (T 3 ) contains liothyronine (L-triiodothyronine or L-T 3 ), a synthetic form of a natural thyroid hormone, as the sodium salt. The structural and empirical formulas and molecular weight of liothyronine sodium are given below. 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 liothyronine sodium injection (T 3 ) in amber glass vials contains, in sterile non-pyrogenic aqueous solution, liothyronine sodium equivalent to 10 mcg of liothyronine; alcohol, 6.8% by volume; anhydrous citric acid, 0.175 mg; ammonia, 2.19 mg, as ammonium hydroxide; Water for Injection, USP. C:\Documents and Settings\junem.X-GEN.000\Desktop\Lio SPL\FDA Style sheets\01.jpg

AND USAGE Liothyronine sodium is an L-triiodothyronine (T3) indicated for: Hypothyroidism: As replacement in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism ( 1.1 )

Pituitary

Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct to surgery and radioiodine therapy in the management of well-differentiated thyroid cancer ( 1.2 )

Thyroid Suppression

Test: As a diagnostic agent in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy ( 1.3 ) Limitations of Use: - Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients. ( 1 ) - Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. ( 1 )

1.1 Hypothyroidism Liothyronine Sodium Tablets, USP are indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

1.2 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH)

Suppression Liothyronine Sodium

Tablets, USP are indicated as an adjunct to surgery and radioiodine therapy in the management of well-differentiated thyroid cancer.

1.3 Thyroid Suppression Test Liothyronine Sodium Tablets, USP are indicated as a diagnostic agent in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy. Limitations of Use Liothyronine Sodium Tablets, USP are not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and overtreatment with Liothyronine Sodium Tablets, USP may induce hyperthyroidism <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>.

Liothyronine Sodium

Tablets, USP are not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

AND ADMINISTRATION Administer Liothyronine Sodium Tablets, USP orally once daily and individual dosage according to patient response and laboratory findings ( 2.1 ) See full prescribing information for recommended dosage for hypothyroidism ( 2.2 ) TSH suppression in well-differentiated thyroid cancer ( 2.3 ) and for thyroid suppression test ( 2.4 ) When switching a patient to Liothyronine Sodium Tablets, USP discontinue levothyroxine therapy and initiate Liothyronine Sodium Tablets, USP at a low dosage. Gradually increase the dose according to the patient's response ( 2.5 ) Adequacy of therapy determined with periodic monitoring of TSH and T3 levels as well as clinical status ( 2.6 )

2.1 General Principles of Dosing The dose of Liothyronine Sodium Tablets, USP for hypothyroidism or pituitary Thyroid-Stimulating Hormone (TSH) suppression depends on a variety of factors including: the patient&apos;s age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food and the specific nature of the condition being treated <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 , 2.3 , 2.4 ), Warnings and Precautions (5) , and Drug Interactions (7) ]</span> . Dosing must be individualized to account for these factors and dose adjustments made based on periodic assessment of the patient&apos;s clinical response and laboratory parameters <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span>.

Administer Liothyronine Sodium

Tablets, USP orally once daily.

2.2 Recommended Dosage for Hypothyroidism Adults The recommended starting dosage is 25 mcg orally once daily. Increase the dose by 25 mcg daily every 1 or 2 weeks, if needed. The usual maintenance dose is 25 mcg to 75 mcg once daily. For elderly patients or patients with underlying cardiac disease, start with Liothyronine Sodium Tablets, USP 5 mcg once daily and increase by 5 mcg increments at the recommended intervals. Serum TSH is not a reliable measure of liothyronine sodium dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum T3 level to monitor adequacy of therapy in this patient population.

Pediatric Patients

The recommended starting dosage is 5 mcg once daily, with a 5 mcg increase every 3 to 4 days until the desired response is achieved. Infants a few months old may require 20 mcg once daily for maintenance.

At

1 year of age, 50 mcg once daily may be required.

Above

3 years of age, the full adult dosage may be necessary [see Use in Specific Populations (8.4) ]. Newborns (0 to 3 months) at Risk for Cardiac Failure: Consider a lower starting dose in infants at risk for cardiac failure. Increase the dose as needed based on clinical and laboratory response.

Pediatric

Patients at Risk for Hyperactivity: To minimize the risk of hyperactivity in pediatric patients, start at one-fourth the recommended full replacement dose, and increase on a weekly basis by one-fourth the full recommended replacement dose until the full recommended replacement dose is reached.

Pregnancy

Pre-existing Hypothyroidism: Thyroid hormone dose requirements may increase during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. For patients with serum TSH above the normal trimester-specific range, increase the dose of thyroid hormone and measure TSH every 4 weeks until a stable dose is reached and serum TSH is within the normal trimester-specific range. Reduce thyroid hormone dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure thyroid hormone dose is appropriate.

2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer The dose of Liothyronine Sodium Tablets, USP should target TSH levels within the desired therapeutic range. This may require higher doses, depending on the target level for TSH suppression.

2.4 Recommended Dosage for Thyroid Suppression Test The recommended dose is 75 mcg to 100 mcg daily for 7 days, with radioactive iodine uptake being determined before and after the 7 day administration of Liothyronine Sodium Tablets, USP. If thyroid function is normal, the radioiodine uptake will drop significantly after treatment. A 50% or greater suppression of uptake indicates a normal thyroid-pituitary axis.

2.5 Switching from Levothyroxine to Liothyronine Sodium Tablets, USP Liothyronine sodium has a rapid onset of action and residual effects of the other thyroid preparation may persist for the first several weeks after initiating liothyronine sodium therapy. When switching a patient to Liothyronine Sodium Tablets, USP, discontinue levothyroxine therapy and initiate Liothyronine Sodium Tablets, USP at a low dosage. Gradually increase the liothyronine sodium dose according to the patient&apos;s response.

2.6 Monitoring TSH and Triiodothyronine (T3)

Levels

Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of Liothyronine Sodium Tablets, USP may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors. Adults In adult patients with primary hypothyroidism, monitor serum TSH periodically after initiation of the therapy or any change in dose. To check the immediate response to therapy before the TSH has had a chance to respond or if your patient's status needs to be assessed prior to that point, measurement of total T3 would be most appropriate. In patients on a stable and appropriate replacement dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient's clinical status. Pediatrics In pediatric patients with hypothyroidism, assess the adequacy of replacement therapy by measuring serum TSH and T3 levels. For pediatric patients three years of age and older, the recommended monitoring is every 3 to 12 months thereafter, following dose stabilization until growth and puberty are completed. Poor compliance or abnormal values may necessitate more frequent monitoring. Perform routine clinical examination, including assessment of development, mental and physical growth, and bone maturation, at regular intervals. While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. Failure of the serum TSH to decrease below 20 IU per liter after initiation of liothyronine sodium therapy may indicate the child is not receiving adequate therapy. Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of Liothyronine Sodium Tablets, USP [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)] . Secondary and Tertiary Hypothyroidism Monitor serum T3 levels and maintain in the normal range.

CONTRAINDICATIONS Thyroid hormone preparations are generally contraindicated in patients with diagnosed but as yet uncorrected adrenal cortical insufficiency or untreated thyrotoxicosis. Thyroid hormone preparations are also generally contraindicated in patients with hypersensitivity to any of the active or extraneous constituents of these preparations; however, there is no well-documented evidence in the literature of true allergic or idiosyncratic reactions to thyroid hormone. Concomitant use of liothyronine sodium injection (T 3 ) and artificial rewarming of patients is contraindicated. (See PRECAUTIONS .)

REACTIONS Adverse reactions associated with liothyronine sodium therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5.4) and Overdosage (10) ] . They include the following: General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia Musculoskeletal : tremors, muscle weakness and cramps Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest Respiratory: dyspnea Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests Dermatologic: hair loss, flushing Endocrine: decreased bone mineral density Reproductive: menstrual irregularities, impaired fertility Adverse Reactions in Pediatric Patients Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving thyroid replacement therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in pediatric patients with resultant compromised adult height.

Hypersensitivity Reactions

Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. To report SUSPECTED ADVERSE REACTIONS , contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions for Liothyronine Sodium Tablets, USP are primarily those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

AND PRECAUTIONS Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate liothyronine sodium tablets at less than the full replacement dose because of the increased risk of cardiac adverse reactions, including atrial fibrillation ( 2.3 , 5.1 , 8.5 ) Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. ( 5.2 ) Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement glucocorticoids prior to initiation of liothyronine sodium tablets treatment ( 5.3 ) Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper dose titration and careful monitoring is critical to prevent the persistence of hypothyroidism or the development of hyperthyroidism. (5.4 ) Worsening of diabetic control: Therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing thyroid hormone therapy ( 5.5 ) Decreased bone mineral density associated with thyroid hormone over-replacement: Over-replacement can increase bone resorption and decrease bone mineral density. Give the lowest effective dose ( 5.6 )

5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Overtreatment with thyroid hormone may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate liothyronine sodium tablets therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Use in Specific Populations (8.5)]</span> . Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive liothyronine sodium tablets therapy. Monitor patients receiving concomitant liothyronine sodium tablets and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiovascular symptoms develop or worsen, reduce or withhold the liothyronine sodium tablets dose for one week and restart at a lower dose.

5.2 Myxedema Coma Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of thyroid hormone from the gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma.

5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with liothyronine sodium tablets <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism Liothyronine sodium has a narrow therapeutic index. Over- or undertreatment with liothyronine sodium tablets may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Titrate the dose of liothyronine sodium tablets carefully and monitor response to titration to avoid these effects <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> . Monitor for the presence of drug or food interactions when using liothyronine sodium tablets and adjust the dose as necessary <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )]</span> .

5.5 Worsening of Diabetic Control Addition of thyroid hormone therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing liothyronine sodium tablets <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement Increased bone resorption and decreased bone mineral density may occur as a result of thyroid hormone over-replacement, particularly in post-menopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Administer the minimum dose of liothyronine sodium tablets that achieves the desired clinical and biochemical response to mitigate against this risk.

PRECAUTIONS General - 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. 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. In infants, excessive doses of thyroid hormone preparations may produce craniosynostosis. Information for the Patient - Patients on thyroid hormone preparations and parents of pediatric patients 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 pediatric patients 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 T 4 levels can be used to test the effectiveness of all thyroid medications except products containing liothyronine sodium. When the total serum T 4 is low but TSH is normal, a test specific to assess unbound (free) T 4 levels is warranted. Specific measurements of T 4 and T 3 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 T 4 by column.

Drug Interactions 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 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 - Cholestyramine binds both T 4 and T 3 in the intestine, thus impairing absorption of these thyroid hormones. In vitro studies indicate that the binding is not easily removed. Therefore, 4 to 5 hours should elapse between administration of cholestyramine 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.

Tricyclic

Antidepressants - Use of thyroid products with imipramine and other tricyclic antidepressants may increase receptor sensitivity and enhance antidepressant activity; transient cardiac arrhythmias have been observed. Thyroid hormone activity may also be enhanced. Digitalis - Thyroid preparations may potentiate the toxic effects of digitalis. Thyroid hormonal replacement increases metabolic rate, which requires an increase in digitalis dosage. Ketamine - When administered to patients on a thyroid preparation, this parenteral anesthetic may cause hypertension and tachycardia. Use with caution and be prepared to treat hypertension, if necessary. Vasopressors - Thyroxine increases the adrenergic effect of catecholamines such as epinephrine and norepinephrine. Therefore, injection of these agents into patients receiving thyroid preparations increases the risk of precipitating coronary insufficiency, especially in patients with coronary artery disease. Careful observation is required.

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 T 4 and T 3 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 hypothyroxine-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.

Geriatric

Use - Clinical studies of liothyronine sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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 T 4 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.

INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to liothyronine sodium tablets ( 7 )

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to liothyronine sodium tablets (see Tables 1 to 4).

Table

1: Drugs That May Decrease T3 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of liothyronine sodium tablets by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Bile Acid Sequestrants -Colesevelam -Cholestyramine -Colestipol Ion Exchange Resins -Kayexalate -Sevelamer Bile acid sequestrants and ion exchange resins are known to decrease thyroid hormones absorption. Administer liothyronine sodium tablets at least 4 hours prior to these drugs or monitor thyrotropin-stimulating hormone (TSH) levels.

Table

2: Drugs That May Alter Triiodothyronine (T3)

Serum Transport Without Affecting Free

Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class Effect Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen These drugs may increase serum thyroxine-binding globulin (TBG) concentration. Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid These drugs may decrease serum TBG concentration. Salicylates (>2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. Other drugs: Carbamazepine Furosemide (>80 mg IV)

Heparin Hydantoins

Non-Steroidal Anti- inflammatory Drugs - Fenamates These drugs may cause protein binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increased free-T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of thyroid hormones, and total and FT4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.

Table

3: Drugs That May Alter Hepatic Metabolism of Thyroid hormones Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of thyroid hormones, resulting in increased liothyronine sodium tablets requirements. Drug or Drug Class Effect Phenobarbital Rifampin Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5'-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of thyroid hormones.

Table

4: Drugs That May Decrease Conversion of T4 to T3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class Effect Beta-adrenergic antagonists (e.g., Propranolol >160 mg/day) In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. Glucocorticoids (e.g., Dexamethasone ≥4 mg/day) Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). Other drugs: Amiodarone Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.

7.2 Antidiabetic Therapy Addition of liothyronine sodium tablets therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when Liothyronine sodium tablets are started, changed, or discontinued <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

7.3 Oral Anticoagulants Liothyronine sodium tablets increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the liothyronine sodium tablets dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

7.4 Digitalis Glycosides Liothyronine sodium tablets may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides.

7.5 Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and liothyronine sodium tablets may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. liothyronine sodium tablets may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on liothyronine sodium tablets may result in increased liothyronine sodium tablets requirements.

7.6 Ketamine Concurrent use of ketamine and liothyronine sodium tablets may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

7.7 Sympathomimetics Concurrent use of sympathomimetics and liothyronine sodium tablets may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.

7.8 Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients.

7.9 Drug-Laboratory Test Interactions Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.