Brand names: Cytomel, Triostat
Drug class: Thyroid Agents
ATC class: H03AA02
VA class: HS851
CAS number: 55-06-1

Introduction

Synthetic thyroid agent; sodium salt of the l-isomer of 3,3′,5-triiodothyronine (l-T₃).

Uses for Liothyronine

Hypothyroidism

Used orally as replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism.

Generally considered unsatisfactory for long-term use because of potential problems (i.e., wide swings in serum T₃ concentrations, possibility of more pronounced adverse cardiovascular effects); however, may be useful when absorption of levothyroxine is questionable, when impairment of peripheral conversion of thyroxine to triiodothyronine is suspected, or in patients allergic to natural thyroid hormone. Levothyroxine is considered drug of choice for replacement therapy.

For treatment of congenital hypothyroidism (cretinism), levothyroxine is considered drug of choice.

Used IV for treatment of myxedema coma or precoma. Preferred by some clinicians over levothyroxine when a rapid effect or rapidly reversible effect is desired; however, levothyroxine generally is considered drug of choice for this use.

Pituitary TSH Suppression

Treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), and multinodular goiter.

Adjunct to radioiodine therapy in the management of thyroid cancer^{† [off-label]}.

Diagnosis of Thyroid Disorders

Used diagnostically in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy. Use with caution in patients in whom there is a strong suspicion of thyroid gland autonomy because exogenous hormone effects will be additive to endogenous source.

Liothyronine Dosage and Administration

General

• Initially, monitor response to therapy about every 6–8 weeks. Once normalization of thyroid function and serum TSH concentrations have been achieved, patients may be evaluated less frequently (i.e., every 6–12 months). However, if dosage is changed, measure serum TSH concentrations after 8–12 weeks.

• Natural and synthetic thyroid agent preparations are not necessarily directly comparable; however, the following equivalencies have been suggested based on clinical response:

• When switching from another thyroid preparation to liothyronine, discontinue the other preparation, then initiate liothyronine therapy at a low dosage and titrate as needed in small increments after the residual effects of the previous thyroid preparation have subsided.

  When switching from liothyronine to another thyroid preparation, consider the rapid onset and dissipation of effects of liothyronine and, to avoid relapse, start therapy with the replacement thyroid preparation several days before complete withdrawal of liothyronine.

Administration

Administer orally or by IV injection. Do not administer IM or sub-Q.

Oral Administration

Administer orally once daily.

NG Tube

Has been administered orally via NG tube for treatment of myxedema coma; however, IV administration is preferred.

IV Administration

IV administration may be necessary when oral administration is not feasible or desirable (e.g., in the treatment of myxedema coma, in some neonates, during total parenteral nutrition). Replace with oral therapy as soon as possible.

Dosage

Available as liothyronine sodium; dosage expressed in terms of liothyronine.

Each 25 mcg of liothyronine is approximately clinically equivalent to 60–65 mg of thyroid or thyroglobulin or 100 mcg or less of levothyroxine. (See General under Dosage and Administration.)

Adjust dosage carefully according to clinical and laboratory response to treatment. Avoid undertreatment or overtreatment. (See Therapy Monitoring under Cautions.)

Initiate at a lower dosage level in geriatric patients, in patients with functional or ECG evidence of cardiovascular disease, and in patients with severe, long-standing hypothyroidism or other endocrinopathies.

Pediatric Patients

Hypothyroidism

Oral

Initiate therapy as soon as possible after diagnosis of hypothyroidism to prevent deleterious effects on intellectual and physical growth and development.

Recommended initial dosage is 5 mcg once daily. Increase by increments of 5 mcg daily at intervals of 3–4 days until desired response is obtained.

Maintenance dosage: Infants a few months old may require only 20 mcg daily. At 1 year of age, 50 mcg daily may be required. At >3 years of age, full adult daily dosage may be required.

Adults

Hypothyroidism

Oral

For management of mild hypothyroidism, recommended initial dosage is 25 mcg once daily. Increase by increments of 12.5 or 25 mcg daily at intervals of 1–2 weeks until desired response is obtained. Usual maintenance dosage is 25–75 mcg daily; some patients may require higher or lower dosages.

For management of severe hypothyroidism (e.g., myxedema), recommended initial dosage is 5 mcg once daily. Increase by increments of 5–10 mcg daily at intervals of 1–2 weeks. When a dosage of 25 mcg daily is reached, may increase by 5–25 mcg daily at intervals of 1 or 2 weeks until desired response is obtained. Usual maintenance dosage is 50–100 mcg once daily.

Myxedema Coma or Precoma

IV, then Oral

In patients who do not have severe cardiovascular disease, recommended initial dose is 25–50 mcg IV. A dosage of ≥65 mcg IV daily in the initial days of therapy reportedly associated with lower mortality; however, clinical experience with dosages >100 mcg daily is limited.

Because of potentially wide swings in serum T₃ concentrations (possibly precipitating adverse cardiovascular effects), adjust dosage with caution. Administer additional doses ≥4 hours apart to allow for adequate assessment of therapeutic response, but no more than 12 hours should elapse between doses to avoid fluctuations in hormone levels.

Replace with oral therapy as soon as patient’s condition stabilizes and drug can be given orally.

When switching from IV to oral liothyronine therapy, discontinue IV liothyronine, then initiate oral liothyronine at low dosage and increase gradually according to patient’s response.

When switching from IV liothyronine to oral levothyroxine therapy, consider delay (several days) in onset of activity of levothyroxine and discontinue IV liothyronine gradually.

Pituitary TSH Suppression

Simple (Nontoxic) Goiter

Oral

Recommended initial dosage is 5 mcg daily. Increase by increments of 5–10 mcg daily at intervals of 1–2 weeks. When a dosage of 25 mcg daily is reached, may increase by 12.5 or 25 mcg daily at intervals of 1–2 weeks until desired response is obtained.

Usual maintenance dosage is 75 mcg daily.

Diagnosis of Thyroid Disorders

Oral

75–100 mcg daily for 7 days. Perform radioactive I 131 uptake test before and after administration of the 7-day course of liothyronine. A ≥50% reduction of I 131 uptake after treatment indicates a normal thyroid-pituitary axis and thus rules out thyroid gland autonomy.

Prescribing Limits

Adults

Myxedema Coma

IV

Limited clinical experience with dosages >100 mcg daily.

Special Populations

Patients with Cardiovascular Disease

Hypothyroidism

Initiate therapy at lower dosages than those recommended for patients without cardiovascular disease.

Usual initial dosage is 5 mcg daily. Increase by increments of 5 mcg at intervals of 2 weeks until desired response is obtained. If cardiovascular disease is aggravated, reduce dosage or temporarily withhold therapy and then cautiously restart therapy at a lower dosage.

Myxedema Coma

If liothyronine therapy is clinically indicated, smaller initial IV doses (i.e., 10–20 mcg) may be necessary. Titrate dosage gradually.

Geriatric Patients

Hypothyroidism

Initiate therapy at lower dosages than those recommended for younger patients.

Usual initial dosage is 5 mcg once daily. Increase by increments of 5 mcg at intervals of 1–2 weeks until desired response is obtained. If cardiovascular disease is aggravated, reduce dosage or temporarily withhold therapy and then cautiously restart therapy at a lower dosage.

Myxedema Coma

Reduced initial IV dose may be appropriate in geriatric patients because of increased risk of cardiovascular disease.

Cautions for Liothyronine

Contraindications

• Untreated thyrotoxicosis.

• AMI uncomplicated by hypothyroidism.

• Uncorrected adrenal insufficiency.

• Concomitant use of IV liothyronine with artificial rewarming of patients.

• Known hypersensitivity to any ingredient in the formulation. (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Unlabeled Uses

Should not be used for the treatment of obesity or for weight loss either alone or with other therapeutic agents. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or life-threatening toxicity, particularly when given in conjunction with sympathomimetic amines (e.g., anorectic agents).

Should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.

Sensitivity Reactions

Hypersensitivity to thyroid hormone is not known to occur. However, hypersensitivity reactions to inactive ingredients of thyroid hormone products have been reported and include urticaria, pruritus, rash, flushing, angioedema, abdominal pain, nausea, vomiting, diarrhea, fever, arthralgia, serum sickness, and wheezing. Allergic skin reactions to liothyronine tablets have been reported rarely.

General Precautions

Therapy Monitoring

Thyroid agents have a narrow therapeutic index. Avoid undertreatment or overtreatment, which may result in adverse effects on growth and development in pediatric patients, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, GI function, and glucose and lipid metabolism.

Periodically perform appropriate laboratory tests (e.g., serum TSH, total T₃) and clinical evaluations to monitor adequacy of therapy.

Preexisting Cardiovascular Disease

Use with extreme caution. (See Patients with Cardiovascular Disease under Dosage and Administration.) Potential for cardiotoxicity may be greater than with preparations that do not contain T₃. Patients with CHD should be monitored closely during surgical procedures due to increased risk of arrhythmias.

Associated Endocrine Disorders

Hypopituitarism, adrenal insufficiency, and other endocrine disorders such as diabetes mellitus and diabetes insipidus are characterized by signs and symptoms which may be diminished in severity or obscured by hypothyroidism. Thyroid agents may aggravate the intensity of previously obscured symptoms in patients with endocrine disorders, and appropriate adjustment of therapy for these concomitant disorders may be required.

In patients with secondary or tertiary hypothyroidism, consider possibility of additional hypothalamic/pituitary hormone deficiencies and treat if diagnosed.

Chronic autoimmune thyroiditis may occur in association with other autoimmune disorders (e.g., adrenal insufficiency, pernicious anemia, type 1 diabetes mellitus).

Patients with concomitant adrenal insufficiency should be treated with replacement corticosteroids prior to initiation of thyroid agents. Failure to do so may precipitate an acute adrenal crisis due to increased metabolic clearance of corticosteroids when the thyroid agent is initiated.

Patients with diabetes mellitus may require increased dosages of antidiabetic agents when treated with liothyronine.

Specific Populations

Pregnancy

Category A.

During pregnancy, serum free tetraiodothyronine (thyroxine, T₄) levels may decrease and serum TSH levels increase to values outside the normal range. Elevations in serum TSH may occur at 4 weeks’ gestation; monitor TSH levels during each trimester (or every 6 weeks) and adjust liothyronine dosage accordingly. Reduce dosage to pre-pregnancy level immediately after delivery, since postpartum TSH concentrations are similar to preconception levels; measure serum TSH concentrations 6–8 weeks postpartum.

Lactation

Although thyroid hormones are distributed minimally into human milk, exercise caution when administering to a nursing woman. However, adequate replacement dosages generally are needed to maintain normal lactation.

Pediatric Use

Safety and efficacy of IV liothyronine not established in pediatric patients.

The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development. Initiate therapy immediately upon diagnosis. Maintain therapy for life, unless transient hypothyroidism is suspected.

Neonates with suspected hypothyroidism should receive thyroid agent therapy pending results of confirmative tests. If a positive diagnosis cannot be made on the basis of laboratory findings but there is a strong clinical suspicion of congenital hypothyroidism, initiate replacement therapy to achieve euthyroidism until the child is 1–2 years of age. During the first 2 weeks of therapy, closely monitor infants for cardiac overload, arrhythmias, and aspiration resulting from avid suckling. Evaluate infant’s clinical response to therapy about 6 weeks after initiation of thyroid agent therapy and at least at 6 and 12 months of age and yearly thereafter.

When transient hypothyroidism is suspected, temporarily discontinue therapy for 2–8 weeks to reassess the condition when the child is >3 years of age. If the diagnosis of permanent hypothyroidism is confirmed, reinstitute full replacement therapy. However, if serum concentrations of T₄ and TSH are normal, discontinue thyroid agent therapy and monitor carefully; repeat thyroid function tests if manifestations of hypothyroidism develop.

In pediatric patients with transient severe hypothyroidism, reduce replacement dose by half for 30 days to reasses condition. If, after 30 days, serum TSH is >20 mU/L, consider the hypothyroidism permanent and reinstitute full replacement therapy. However, if serum TSH has not increased, temporarily discontinue thyroid agent therapy for another 30 days, then repeat serum T₄ and TSH measurements. Reinstitute or discontinue replacement therapy based on laboratory findings.

Monitor patients closely to avoid undertreatment or overtreatment. Undertreatment may result in impaired intellectual development, poor school performance (due to impaired concentration and slowed mentation), and reduced adult height. Overtreatment may result in craniosynostosis in infants and accelerate aging of bones, resulting in premature epiphyseal closure and compromised adult stature.

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to achieve normal adult height. In children with severe or long-standing hypothyroidism, catch-up growth may not be adequate to achieve normal adult height.

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving thyroid agents.

Geriatric Use

Because of the increased risk of cardiovascular disease among geriatric patients, liothyronine therapy should not be initiated at the full replacement dose. (See Geriatric Patients under Dosage and Administration.)

Because of age-related decreases in renal function, may be useful to monitor renal function.

Common Adverse Effects

Adverse reactions result from overdosage and resemble manifestations of hyperthyroidism, including fatigue, weight loss, increased appetite, heat intolerance, fever, excessive sweating, headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia, tremor, muscle weakness, palpitations, tachycardia, arrhythmias, increased heart rate and BP, heart failure, angina, AMI, cardiac arrest, diarrhea, vomiting, abdominal cramps, elevations in liver function test results, hair loss, flushing, decreased bone mineral density, menstrual irregularities, and impaired fertility.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Potential increased metabolism of thyroid agent with drugs that induce hepatic microsomal enzymes resulting in increased thyroid agent dosage requirements.

Drugs That May Decrease T4 5’-Deiodinase Activity

Inhibitors of T₄ 5’-deiodinase decrease peripheral conversion of T₄ to T₃, resulting in decreased T₃ concentrations. However, serum T₄ concentrations usually remain within normal range but may occasionally be slightly increased.

Specific Drugs

Drugs Affecting Thyroid Function or Thyroid Function Tests

Various drugs or concomitant medical conditions (e.g., pregnancy, infectious hepatitis) may adversely affect thyroid function (e.g., alter endogenous thyroid hormone secretion, reduce TSH secretion) resulting in hypothyroidism or hyperthyroidism or interfere with laboratory tests used to assess thyroid function. Consult specialized references for information.

Some drugs may affect transport of thyroid hormones (T₃, T₄) by affecting serum thyroxine-binding globulin (TBG) concentrations. However, free T₄ concentrations may remain normal and the patient may remain euthyroid.

Drugs Affecting Thyroxine Binding Globulin Concentrationsb c d

Drugs That May Increase Serum TBG Concentration

• Estrogens, oral (including estrogen-containing oral contraceptives)

• Fluorouracil

• Methadone

• Mitotane

• Tamoxifen

Drugs That May Decrease Serum TBG Concentration

• Androgens

• Asparaginase

• Glucocorticoids

• Niacin (extended-release)

Liothyronine Pharmacokinetics

Absorption

Bioavailability

Almost completely absorbed from the GI tract (about 95%).

Onset

More rapid onset of action than levothyroxine. Following a single IV dose, metabolic response is detectable within 2–4 hours and peak therapeutic effects occur within 2 days.

Duration

Shorter duration of action than levothyroxine.

Distribution

Extent

Thyroid hormones do not readily cross the placenta; however, some transfer does occur, as evidenced by levels in cord blood of athyrotic fetuses being approximately one-third maternal levels.

Minimally distributed into breast milk.

Plasma Protein Binding

Circulating thyroid hormones are >99% bound to plasma proteins, including TBG, thyroxine-binding prealbumin (TBPA), and albumin. T₃ is less extensively and firmly bound to TBG and TBPA than T₄. Only unbound hormone is metabolically active.

Elimination

Metabolism

T₃ is metabolized principally in the liver through deiodination to diiodothyronine.

Elimination Route

Thyroid hormones are primarily eliminated by the kidneys.

Half-life

Approximately 1–2 days. Plasma half-life is decreased in patients with hyperthyroidism and increased in those with hypothyroidism.

Stability

Storage

Oral

Tablets

Tight containers at 15–30°C.

Parenteral

Injection

2–8°C.

Actions

• Thyroid hormones (T₄ and T₃) regulate multiple metabolic processes, including augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates, and lipids.

• Thyroid hormones also play an essential role in normal growth and development and normal maturation of the CNS and bone. The protein anabolic effects of thyroid hormones are essential for normal growth and development.

• The physiologic actions of thyroid hormones are produced predominately by T₃, most of which (approximately 80%) is derived from T₄ by deiodination in peripheral tissues.

• T₃ is 4 times more potent than T₄.

Advice to Patients

• Importance of understanding the need to continue thyroid agent therapy for life, unless transient hypothyroidism is suspected.

• Importance of taking liothyronine exactly as prescribed. Do not alter regimen or discontinue therapy unless directed by a clinician.

• Risk of transient hair loss. Importance of immediately informing a clinician if rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event occurs.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, clotting disorders, adrenal or pituitary gland problems).

• In patients with diabetes mellitus, importance of monitoring blood and/or urinary glucose levels and immediately reporting any changes to a clinician. In patients receiving concomitant anticoagulant therapy, importance of monitoring clotting status frequently.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Dosage may need to be increased during pregnancy.

• Importance of informing physician or dentist of current thyroid hormone therapy prior to any surgery.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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