Brand names: Levothroid, Levoxyl, Synthroid, Unithroid
Drug class: Thyroid Agents
VA class: HS851
CAS number: 25416-65-3

Medically reviewed by Drugs.com on Nov 27, 2024. Written by ASHP.

Introduction

Thyroid agent; sodium salt of the l-isomer of thyroxine (tetraiodothyronine, T₄).

Uses for Levothyroxine

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 subclinical hypothyroidism and primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism.

Considered drug of choice for the treatment of congenital hypothyroidism (cretinism).

Used IV for treatment of myxedema coma.

Has been used IV in other conditions when rapid thyroid replacement is required^{† [off-label]}; however, this is not an FDA-labeled use for the currently available injection.

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 surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Efficacy of TSH suppression for benign nodular disease remains controversial.

Other Uses

See Unlabeled Uses under Cautions.

Levothyroxine Dosage and Administration

General

• Approved levothyroxine sodium oral preparations should be considered therapeutically inequivalent unless equivalence has been established and noted in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). Check Orange Book at [Web] for more current information on preparations designated therapeutically equivalent by the FDA.

• Due to narrow therapeutic index, American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE) recommend not to use levothyroxine sodium preparations interchangeably. When switching preparations (e.g., from brand to generic), pharmacists should notify the patient and prescriber. In addition, clinicians should measure serum TSH concentration about 4–8 weeks after starting the new preparation and adjust dosage if needed.

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

Administration

Administer orally or by IV injection. The drug also has been administered by IM injection^{† [off-label]}; however, IV is preferred since absorption may be variable following IM administration.

Oral Administration

Administer orally on an empty stomach, preferably one-half to one hour before breakfast or the first food of the day. Administer Levoxyl tablets with a full glass of water to avoid choking, gagging, or difficulty in swallowing the tablet.

In individuals who are unable to swallow intact tablets (e.g., pediatric patients), may crush appropriate dose of levothyroxine tablets and place in a small amount (5–10 mL) of water; immediately administer resultant suspension by spoon or dropper (do not store).

Foods that decrease absorption of levothyroxine (e.g., soybean infant formula, soybean flour, cotton seed meal) should not be used for administering levothyroxine.

IV Administration

For solution compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute powder for injection by adding 5 mL of 0.9% sodium chloride injection to vial containing 100, 200, or 500 mcg levothyroxine sodium; shake until clear solution is obtained. Resultant solutions contain approximately 20, 40, or 100 mcg/mL, respectively.

Use reconstituted solutions immediately and discard any unused portions; do not admix with IV infusion solutions. (See Powder for Injection under Stability.)

Dosage

Available as levothyroxine sodium; dosage is expressed in terms of the salt.

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

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

Use caution when switching patients from oral to IV administration; relative bioavailability and accurate dosing conversion between oral and IV preparations not established.

Pediatric Patients

Hypothyroidism

Oral

Initiate therapy at full replacement dosages as soon as possible after diagnosis of hypothyroidism to prevent deleterious effects on intellectual and physical growth and development; initiate dosage at a lower level in children with long-standing or severe hypothyroidism. The following dosages have been recommended:

In neonates at risk of cardiac failure, initiate at a lower dosage (e.g., 25 mcg daily); increase dosage at intervals of 4–6 weeks as needed based on clinical and laboratory response to treatment. In neonates with very low (<5 mcg/dL) or undetectable serum T₄ concentrations, usual initial dosage is 50 mcg daily.

When transient hypothyroidism is suspected, therapy may be temporarily discontinued when the child is older than 3 years of age to reassess the condition. (See Pediatric Use under Cautions.)

Hyperactivity in an older child may be minimized by initiating therapy at a dosage approximately one-fourth of the recommended full replacement dosage; increase dosage by an amount equal to one-fourth the full recommended replacement dosage at weekly intervals until the full recommended replacement dosage is reached.

For treatment of severe or long-standing hypothyroidism, usual initial dosage is 25 mcg daily. Increase dosage in increments of 25 mcg at intervals of 2–4 weeks until desired response is obtained.

Adults

Hypothyroidism

Oral

In otherwise healthy individuals <50 years of age and in those >50 years of age who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (i.e., several months), usual initial oral dosage (full replacement dosage) is 1.7 mcg/kg daily (e.g., 100–125 mcg daily for a 70-kg adult) given as a single dose. Older patients may require <1 mcg/kg daily.

Dosages >200 mcg daily seldom required; failure to respond adequately to oral dosages ≥ 300 mcg daily is rare and should prompt reevaluation of the diagnosis, or suggest presence of malabsorption, patient noncompliance, and/or drug interactions.

For most patients >50 years of age, usual initial dosage is 25–50 mcg daily given as a single dose; increase dosage at intervals of 6–8 weeks.

For management of severe or long-standing hypothyroidism, usual initial dosage is 12.5–25 mcg daily given as a single dose. Increase by increments of 25 mcg at intervals of 2–4 weeks until serum TSH concentrations return to normal; some clinicians suggest that dosage be adjusted at intervals of 4–8 weeks.

For management of subclinical hypothyroidism (if considered necessary), initiate at lower dosages (e.g., 1 mcg/kg daily). If levothyroxine therapy is not initiated, monitor patients annually for changes in clinical status and thyroid laboratory parameters.

Myxedema Coma

IV

Consider the patient's age, general physical condition, and cardiac risk factors, as well as the clinical severity and duration of myxedema symptoms when selecting initial and maintenance dosages.

Initial loading dose is 300–500 mcg; some clinicians recommend an initial dose of 100–500 mcg.

Maintenance dosage: 50–100 mcg daily as clinically indicated until patient’s condition stabilizes and drug can be given orally.

Use caution when switching patients from oral to IV levothyroxine; relative bioavailability and accurate dosing conversion between oral and IV preparations not established.

Pituitary TSH Suppression

Individualize dosage based on patient characteristics and nature of the disease. Target level for TSH suppression in management of well-differentiated thyroid cancer and thyroid nodules not established.

Thyroid Cancer

Oral

Dosages >2 mcg/kg daily given as a single dose usually required to suppress TSH concentrations to <0.1 mU/L. In patients with high-risk tumors, target level for TSH suppression may be <0.01 mU/L.

Benign Nodules or Nontoxic Multinodular Goiter

Oral

Suppress TSH concentrations to 0.1–0.5 mU/L for nodules and to 0.5–1 mU/L for multinodular goiter.

Special Populations

Patients with Cardiovascular Disease

Hypothyroidism

Oral: Initiate therapy at lower doses than those recommended in patients without cardiovascular disease. For patients <50 years of age with underlying cardiovascular disease, usual initial dosage is 25–50 mcg once daily; increase dosage at intervals of 6–8 weeks.

If cardiac symptoms develop or worsen, reduce dosage or withhold therapy for 1 week and then cautiously restart therapy at a lower dose.

Myxedema Coma

IV: Excessive bolus doses >500 mcg associated with cardiac complications, particularly in patients with underlying cardiac conditions.

Cautious use (e.g., smaller IV doses) may be warranted.

Geriatric Patients

Hypothyroidism

Oral: Initiate therapy at lower doses than those recommended in younger patients.

In geriatric patients with underlying cardiovascular disease, usual initial dosage is 12.5–25 mcg daily; increase dosage by increments of 12.5–25 mcg at intervals of 4–6 weeks until patient becomes euthyroid and serum TSH concentrations return to normal. If cardiac symptoms develop or worsen, reduce dosage or withhold therapy for 1 week and then cautiously restart therapy at a lower dose.

Myxedema Coma

IV: Excessive bolus doses >500 mcg associated with cardiac complications.

Cautious use (e.g., smaller IV doses) may be warranted.

Cautions for Levothyroxine

Contraindications

Oral

• Untreated subclinical (suppressed serum TSH concentrations with normal T₃ [triiodothyronine] and T₄ concentrations) or overt thyrotoxicosis of any etiology.

• AMI.

• Untreated adrenal insufficiency.

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

IV

• Manufacturer states none.

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.

Thyrotoxicosis

Because of risk of precipitating overt thyrotoxicosis, levothyroxine is contraindicated in patients with nontoxic diffuse goiter or nodular thyroid disease (particularly geriatric patients or those with underlying cardiovascular disease) in whom serum TSH level is already suppressed.

If serum TSH level is not suppressed, use with caution and monitor clinical (e.g., adverse cardiovascular effects) and laboratory (i.e., thyroid function) parameters for evidence of hyperthyroidism.

Sensitivity Reactions

Hypersensitivity to levothyroxine 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.

Major Toxicities

Effects on Bone Mineral Density

In women, long-term therapy has been associated with decreased bone mineral density, especially in postmenopausal women receiving greater than replacement doses or in women who are receiving suppressive doses. Use lowest dose necessary to achieve desired clinical and biochemical response.

GI Effects

Choking, gagging, dysphagia, or lodging of a tablet in the throat reported with Levoxyl, particularly when administered without water. Administer Levoxyl tablets with a full glass of water.

General Precautions

Therapy Monitoring

Levothyroxine has 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 or free T₄) and clinical evaluations to monitor adequacy of therapy.

Preexisting Cardiovascular Disease

Use with caution. (See Patients with Cardiovascular Disease under Dosage and Administration.) Patients with CHD should be monitored closely during surgical procedures due to increased risk of arrhythmias.

Excessive IV bolus doses (i.e., >500 mcg) are associated with cardiac complications (e.g., arrhythmias, tachycardia, myocardial ischemia and infarction, worsening CHF, death), particularly in geriatric patients and in patients with underlying cardiac conditions. (See Special Populations under Dosage and Administration.) Closely observe patient following IV administration.

Associated Endocrine Disorders

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

Chronic autoimmune thyroiditis, which can lead to myxedema coma, may occur in association with other autoimmune disorders (e.g., adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus).

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

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

Patients with myxedema coma also should be treated with replacement glucocorticoids until adrenal function has been adequately assessed; monitor for previously undiagnosed diabetes insipidus upon initiation of IV levothyroxine.

Lactose Intolerance

Lactose is used in manufacture of Synthroid and Unithroid tablets.

Specific Populations

Pregnancy

Category A.

During pregnancy, serum 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 and adjust levothyroxine sodium 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.

Myxedema coma: Manufacturer states there are no reports of levothyroxine injection use in pregnant women with myxedema coma; however, there is no evidence of increased fetal abnormalities with oral use of the drug to maintain euthyroid state. Nontreatment of myxedema is associated with a high probability of maternal or fetal morbidity or mortality; therefore, pregnant patients who develop myxedema should be treated with IV levothyroxine.

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.

Myxedema coma: Manufacturer states there are no reports of levothyroxine injection use in lactating women with myxedema coma. However, such patients should be treated with IV levothyroxine because nontreatment is associated with a high probability of morbidity or mortality.

Pediatric Use

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 and maintain 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 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 levothyroxine and at least at 6 and 12 months of age and yearly thereafter.

When transient hypothyroidism is suspected, temporarily discontinue therapy for 4–8 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 levothyroxine 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. If, after 30 days, serum TSH >20 mU/L, consider the hypothyroidism permanent and reinstitute full replacement therapy. However, if serum TSH ≤ 20 mU/L, temporarily discontinue levothyroxine for 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 levothyroxine.

Manufacturer of IV levothyroxine states that myxedema coma is a disease of the elderly; an approved oral dosage form should be used in pediatric patients with noncomplicated hypothyroidism to maintain euthyroid state.

Geriatric Use

Because of the increased risk of cardiovascular disease among geriatric patients, levothyroxine therapy should not be initiated at the full replacement dose.

Myxedema coma: Select IV dosage with caution, and closely observe patient. (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Adverse reactions result from overdosage and resemble manifestations of hyperthyroidism, including fatigue, increased appetite, weight loss, 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, dyspnea, diarrhea, vomiting, abdominal cramps, elevations in liver function tests, hair loss, flushing, decreased bone mineral density, menstrual irregularities, and impaired fertility.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Potential increased levothyroxine metabolism and decreased plasma levothyroxine concentrations with drugs that induce general hepatic metabolic activity resulting in increased levothyroxine 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 and Foods

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, levothyroxine) by affecting serum thyroxine-binding globulin (TBG) concentrations. However, free T₄ concentrations may remain normal and the patient may remain euthyroid. Monitor therapy and adjust levothyroxine dosages as necessary.

Drugs Affecting Thyroxine Binding Globulin Concentration140 141 142 160 165

The following drugs may increase serum TBG concentrations:

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

• Fluorouracil

• Methadone

• Mitotane

• Tamoxifen

The following drugs may decrease serum TBG concentrations:

• Androgens

• Asparaginase

• Glucocorticoids

• Niacin (sustained-release)

Levothyroxine Pharmacokinetics

Absorption

Bioavailability

Variably absorbed from the GI tract (range: 40–80%).

Extent of absorption is increased in the fasting state and decreased in malabsorption states (e.g., sprue); absorption also may decrease with age.

Absorption is variable following IM administration. (See Administration under Dosage and Administration.)

Manufacturer of IV levothyroxine states that relative bioavailability between oral and IV administration has been estimated to range from 48–74%.

Currently approved levothyroxine preparations should be considered therapeutically inequivalent unless equivalency has been established and noted in the FDA’s Approved Drug Products with Therapeutic Equivalency Evaluations (Orange Book).

Onset

Due to the long half-life, peak therapeutic effects may not be attained for 4–6 weeks.

Food

Infant soybean formula, soybean flour, cotton seed meal, walnuts, and foods containing large amounts of fiber may decrease absorption of 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. Only unbound hormone is metabolically active.

Elimination

Metabolism

T₄ and T₃ are metabolized principally in the liver through sequential deiodination. Approximately 80% of the daily dose of T₄ is deiodinated to yield equal amounts of T₃ and reverse T₃ (rT₃). T₃ and rT₃ are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.

Elimination Route

Primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T₄ is eliminated in the stool. Urinary excretion of T₄ decreases with age.

Half-life

6–8 days for T₄ (3–4 days in hyperthyroidism; 9–10 days in hypothyroidism).

≤ 2 days for T₃.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C). Protect from heat, moisture, and light.

Parenteral

Powder for Injection

20–25°C. Protect from light.

Following reconstitution, the drug is stable for 4 hours; however, manufacturer states that reconstituted solutions should be used immediately.

Compatibility

Reconstituted solution should not be admixed with IV infusion solutions.

Parenteral

Solution CompatibilityHID

Actions

• Thyroid hormones (tetraiodothyronine [thyroxine, T₄] and triiodothyronine [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 predominantly by T₃, most of which (approximately 80%) is derived from T₄ by deiodination in peripheral tissues.

• T₃ is 4 times more potent than T₄. The ratio of T₄ to T₃ in thyroglobulin is 10–20 to 1.

Advice to Patients

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

• Importance of taking levothyroxine exactly as prescribed; take Levoxyl with a full glass of water. 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 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 their clinician 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 levothyroxine 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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Frequently asked questions

• Does levothyroxine cause weight gain or loss?
• What can I eat for breakfast after taking levothyroxine?
• Can I take other medications with levothyroxine?
• Does levothyroxine cause hair loss?
• How long after taking levothyroxine can you drink milk?
• How long does levothyroxine stay in your system?
• How soon after taking levothyroxine can I take omeprazole?
• What is the difference between Levoxyl and Synthroid?
• What is the difference between Unithroid and Synthroid?

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