Levothyroxine Sodium

Class: Thyroid Agents
VA Class: HS851
CAS Number: 25416-65-3
Brands: Levothroid, Levoxyl, Synthroid, Unithroid

Introduction

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

Uses for Levothyroxine Sodium

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.^{140 141 142 143 161 160} Specific indications include subclinical hypothyroidism and primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism.^{140 141 142 143 161 160}

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

Used IV for treatment of myxedema coma or other conditions when rapid thyroid replacement is required.^{140 141 142 155 161 160}

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.^{140 141 142 161 160}

Adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.^{140 141 142 161 160}

Efficacy of TSH suppression for benign nodular disease remains controversial.^{141 142 160}

Other Uses

See Unlabeled Uses under Cautions.

Levothyroxine Sodium Dosage and Administration

General

• 
  

  Approved levothyroxine sodium oral preparations¹⁵⁷ 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).¹⁴⁴ The following are considered to be therapeutically equivalent to at least 1 reference listed drug: Levoxyl, Synthroid, Unithroid, and nonproprietary (generic) levothyroxine sodium preparations manufactured by Mylan, Sandoz, or Lannett.^{162 163 164} Check Orange Book at 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.^{157 163} When switching preparations (e.g., from brand to generic), pharmacists should notify the patient and prescriber.^{162 163} In addition, clinicians should measure serum TSH concentration about 4–8 weeks after starting the new preparation and adjust dosage if needed.^{162 163}

  
  


• 
  

  Initially, monitor response to therapy about every 6–8 weeks.^{135 140 141 142} Once normalization of thyroid function and serum TSH concentrations has been achieved, patients may be evaluated less frequently (i.e., every 6–12 months).¹³⁵ However, if dosage of levothyroxine is changed, measure serum TSH concentrations after 8–12 weeks.^{135 140 141 142 160}

  
  

Administration

Administer orally or by IV or IM injection.^{140 141 142 143 161 160} IV is preferred over IM since absorption may be variable following IM administration.^a

Oral Administration

Administer orally on an empty stomach, preferably one-half to one hour before breakfast or the first food of the day.^{140 141 142 143 160} Administer Levoxyl tablets with a full glass of water to avoid choking, gagging, or difficulty in swallowing the tablet.¹⁴¹

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).^{140 141 142 152}

Foods that decrease absorption of levothyroxine (e.g., soybean infant formula, soybean flour, cotton seed meal) should not be used for administering levothyroxine.^{140 141 142 160}

IV Administration

For solution compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute Synthroid powder for injection by adding 5 mL of 0.9% sodium chloride injection to vial containing 200 or 500 mcg levothyroxine sodium; shake until clear solution is obtained.¹⁶¹ Resultant solutions contain approximately 40 or 100 mcg/mL, respectively.^a

Alternatively, to produce Synthroid solutions containing approximately 100 mcg/mL, add 2 mL 0.9% sodium chloride injection to vial containing 200 mcg.^a

Use reconstituted solutions immediately and discard any unused portions; do not admix with IV infusion solutions.¹⁶¹

Dosage

Available as levothyroxine sodium; dosage is expressed in terms of the salt.^{140 141 142}

Adjust dosage carefully according to clinical and laboratory response to treatment.^{140 141 142 160} Avoid undertreatment or overtreatment.^{140 141 142 161 160} (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.^{145 146 147}

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.^{140 141 142 160} The following dosages have been recommended:

Dosage for Management of Hypothyroidism in Pediatric Patients140141142152a160

Age	Daily Dose
0–3 months	10–15 mcg/kg
3–6 months	25–50 mcg or 8–10 mcg/kg
6–12 months	50–75 mcg or 6–8 mcg/kg
1–5 years	75–100 mcg or 5–6 mcg/kg
6–12 years	100–150 mcg or 4–5 mcg/kg
Older than 12 years (growth and puberty incomplete)	>150 mcg or 2–3 mcg/kg
Growth and puberty complete	1.6–1.7 mcg/kg

Alternatively, 25–50 mcg once daily has been recommended for otherwise healthy children <1 year of age; after 1 year of age, children may be given 3–5 mcg/kg daily until the adult dosage of about 150 mcg daily is reached in early or mid-adolescence.^a

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.^{140 141 142 143 160} In neonates with very low (<5 mcg/dL) or undetectable serum T₄ concentrations, usual initial dosage is 50 mcg daily.^{140 141 142 152 160}

When transient hypothyroidism is suspected, therapy may be temporarily discontinued when the child is older than 3 years of age to reassess the condition.^{140 141 142 161 160} (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.^{140 141 142 160}

For treatment of severe or long-standing hypothyroidism, usual initial dosage is 25 mcg daily.^{140 141 142 160} Increase dosage in increments of 25 mcg at intervals of 2–4 weeks until desired response is obtained.^{140 141 142 160}

IV or IM

Replacement therapy: initially about one-half previously established oral dosage.¹⁶¹ Monitor patients closely and adjust dosage according to patient’s tolerance and therapeutic response.¹⁶¹

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.^{135 140 141 142 143 160} Older patients may require <1 mcg/kg daily.^{135 140 141 142}

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.^{140 141 142 160}

For most patients >50 years of age, usual initial dosage is 25–50 mcg daily given as a single dose;^{135 140 141 142 143 146 147 150 160} increase dosage at intervals of 6–8 weeks.^{140 141 142 143}

For management of severe or long-standing hypothyroidism, usual initial dosage is 12.5–25 mcg daily given as a single dose.^{140 141 142 160} Increase by increments of 25 mcg at intervals of 2–4 weeks until serum TSH concentrations return to normal;^{140 141 142 160} some clinicians suggest that dosage be adjusted at intervals of 4–8 weeks.^{143 145 147}

For management of subclinical hypothyroidism (if considered necessary), initiate at lower dosages (e.g., 1 mcg/kg daily).^{140 141 142 160} If levothyroxine therapy is not initiated, monitor patients annually for changes in clinical status and thyroid laboratory parameters.^{140 141 142 160}

IV and IM

Replacement therapy: about one-half previously established oral dosage.¹⁶¹ Usual parenteral maintenance dosage is 50–100 mcg daily.¹⁶¹

Monitor patients closely and adjust dosage according to patient’s tolerance and therapeutic response.¹⁶¹

Myxedema Coma

IV

In patients who do not have severe cardiovascular disease, usual initial dose is 200–500 mcg;¹⁶¹ some clinicians recommend an initial dose of 100–500 mcg.¹⁵⁵ If substantial and progressive improvements have not been achieved, administer 100–300 mcg or greater IV on the second day.¹⁶¹ Lower daily IV dosages should then be administered as needed until patient’s condition stabilizes and drug can be given orally.¹⁶¹

Pituitary TSH Suppression

Individualize dosage based on patient characteristics and nature of the disease.^{141 142 160} Target level for TSH suppression in management of well-differentiated thyroid cancer and thyroid nodules not established.^{141 142 160}

Thyroid Cancer

Oral

Dosages >2 mcg/kg daily given as a single dose usually required to suppress TSH concentrations to <0.1 mU/L.^{140 141 142 160} In patients with high-risk tumors, target level for TSH suppression may be <0.01 mU/L.^{141 160}

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.^{140 142 143 160}

Special Populations

Patients with Cardiovascular Disease

Hypothyroidism

Initiate therapy at lower doses than those recommended in patients without cardiovascular disease.^{140 141 142 161 160} For patients <50 years of age with underlying cardiovascular disease, usual initial dosage is 25–50 mcg daily given as a single dose;^{135 140 141 142 143 146 147 150 160} increase dosage at intervals of 6–8 weeks.^{140 141 142 143}

If cardiac symptoms develop or worsen, reduce dosage or withhold therapy for 1 week and then cautiously restart therapy at a lower dose.^{140 141 142 161 160}

Myxedema Coma

IV

If levothyroxine therapy is clinically indicated, smaller initial IV doses may be necessary.¹⁶¹ Consider risks of adverse cardiovascular effects associated with sudden IV administration of large doses of levothyroxine sodium against risks of withholding therapy.¹⁶¹

Geriatric Patients

Hypothyroidism

Initiate therapy at lower doses than those recommended in younger patients.^{140 141 142 161 160}

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.^{140 141 142 160} If cardiac symptoms develop or worsen, reduce dosage or withhold therapy for 1 week and then cautiously restart therapy at a lower dose.^{140 141 142 161 160}

Myxedema Coma

Reduced initial dose may be appropriate in geriatric patients.^{155 161}

Cautions for Levothyroxine Sodium

Contraindications

• 
  

  Untreated subclinical (suppressed serum TSH concentrations with normal T₃ [triiodothyronine] and T₄ concentrations) or overt thyrotoxicosis of any etiology.^{140 141 142 160 161}

  
  


• 
  

  AMI.^{140 141 142 161 160}

  
  


• 
  

  Untreated adrenal insufficiency.^{140 141 142 161 160}

  
  


• 
  

  Known hypersensitivity to any ingredient in the formulation.^{140 141 142 161 160} (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.^{140 141 142 161 160} In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.^{140 141 142 161 160} Larger doses may produce serious or life-threatening toxicity, particularly when given in conjunction with sympathomimetic amines (e.g., anorectic agents).^{140 141 142 161 160}

Should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.^{140 141 142 161 160}

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.^{141 142 161 160}

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.^{141 142 161 160}

Sensitivity Reactions

Hypersensitivity to levothyroxine is not known to occur.^{140 141 142 161 160} 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.^{140 141 142 161 160}

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.^{140 141 142 161 160} Use lowest dose necessary to achieve desired clinical and biochemical response.^{140 141 142 161 160}

GI Effects

Choking, gagging, dysphagia, or lodging of a tablet in the throat reported with Levoxyl, particularly when administered without water.¹⁴¹ Administer Levoxyl tablets with a full glass of water.¹⁴¹

General Precautions

Therapy Monitoring

Levothyroxine has a narrow therapeutic index.^{140 141 142 161 160} 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.^{140 141 142 161 160}

Periodically perform appropriate laboratory tests (e.g., serum TSH, total or free T₄) and clinical evaluations to monitor adequacy of therapy.^{140 141 142 161 160}

Preexisting Cardiovascular Disease

Use with caution.^{140 141 142 161 160} (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.^{140 141 142 161 160}

Associated Endocrine Disorders

In patients with secondary or tertiary hypothyroidism, consider possibility of additional hypothalamic/pituitary hormone deficiencies and treat if diagnosed.^{140 141 142 161 160}

Chronic autoimmune thyroiditis may occur in association with other autoimmune disorders (e.g., adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus).^{140 141 142 161 160}

Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of levothyroxine.^{140 141 142 161 160} Failure to do so may precipitate an acute adrenal crisis due to increased metabolic clearance of glucocorticoids when levothyroxine is initiated.^{140 141 142 161 160}

Patients with diabetes mellitus may require increased dosages of antidiabetic agents when treated with levothyroxine.^{140 141 142 161 160}

Lactose Intolerance

Lactose is used in manufacture of Synthroid and Unithroid tablets.^{140 142}

Specific Populations

Pregnancy

Category A.^{140 141 142 161 160}

During pregnancy, serum T₄ levels may decrease and serum TSH levels increase to values outside the normal range.^{140 141 142 161 160} Elevations in serum TSH may occur at 4 weeks gestation; monitor TSH levels during each trimester and adjust levothyroxine dosage accordingly.^{140 141 142 161 160} 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.^{140 141 142 161 160}

Lactation

Although thyroid hormones are distributed minimally into human milk, exercise caution when administering to a nursing woman.^{140 141 142 161 160} However, adequate replacement dosages generally are needed to maintain normal lactation.^{140 141 142 161 160}

Pediatric Use

The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development.^{140 141 142 161 160} Initiate therapy immediately upon diagnosis and maintain for life, unless transient hypothyroidism is suspected.^{140 141 142 161 160}

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.^{140 141 142 161 160} 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.^{140 141 142 161 160} If the diagnosis of permanent hypothyroidism is confirmed, reinstitute full replacement therapy.^{140 141 142 161 160} However, if serum concentrations of T₄ and TSH are normal, discontinue levothyroxine and monitor carefully; repeat thyroid function tests if manifestations of hypothyroidism develop.^{140 141 142 161 160}

In pediatric patients with transient severe hypothyroidism, reduce replacement dose by half for 30 days.^{140 141 142 161 160} If, after 30 days, serum TSH >20 mU/L, consider the hypothyroidism permanent and reinstitute full replacement therapy.^{140 141 142 161 160} However, if serum TSH ≤ 20 mU/L, temporarily discontinue levothyroxine for 30 days, then repeat serum T₄ and TSH measurements.^{140 141 142 161 160} Reinstitute or discontinue replacement therapy based on laboratory findings.^{140 141 142 161 160}

Monitor patients closely to avoid undertreatment or overtreatment.^{140 141 142 161 160} Undertreatment may result in impaired intellectual development, poor school performance (due to impaired concentration and slowed mentation), and reduced adult height.^{140 141 142 161 160} Overtreatment may result in craniosynostosis in infants and accelerate aging of bones, resulting in premature epiphyseal closure and compromised adult stature.^{140 141 142 161 160}

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.^{140 141 142 161 160}

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine.^{140 141 142 161 160}

Geriatric Use

Because of the increased risk of cardiovascular disease among geriatric patients, levothyroxine therapy should not be initiated at the full replacement dose.^{140 141 142 161 160}

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.^{141 142 161 160}

Interactions for Levothyroxine Sodium

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.^{141 142 161 160}

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.^{140 141 142 161 160} However, serum T₄ concentrations usually remain within normal range but may occasionally be slightly increased.^{140 141 142 161 160}

Specific Drugs and Foods

Drug or Food	Interaction	Comment
Amiodarone	Decreased metabolism of T4 to T3140 141 142 161 160
Anticoagulants, oral (e.g., coumarins)	Potentiation of anticoagulant activity140 141 142 161 160	Carefully monitor PT and adjust anticoagulant dosage accordingly140 141 142 161 160
Antidepressants (tricyclics, tetracyclics, SSRIs)	Increased risk of cardiac arrhythmias and CNS stimulation when used with tricyclics or tetracyclics140 141 142 161 160 Faster onset of action of tricyclics140 141 142 161 160 Sertraline may increase levothyroxine requirements140 141 142 161 160
Antidiabetic agents (biguanides, meglitinides, sulfonylureas, thiazolidediones, insulin)	Levothyroxine may cause increased antidiabetic agent or insulin requirements140 141 142 161 160	Carefully monitor diabetic control, especially when thyroid therapy is initiated, changed, or discontinued140 141 142 161 160
β-Adrenergic blocking agents (e.g., propranolol hydrochloride dosages >160 mg daily)	Decreased metabolism of T4 to T3140 141 142 161 160 Impaired antihypertensive effects when hypothyroid patient is converted to euthyroid state140 141 142 161 160
Bile acid sequestrants (e.g., cholestyramine, colestipol)	Delayed or impaired levothyroxine absorption140 141 142 161 160	Administer levothyroxine at least 4 hours apart from these agents140 141 142 154 161 160
Carbamazepine	Potential increased levothyroxine metabolism140 141 142 161 160 Reduced levothyroxine serum protein binding140 141 142 161 160	May require levothyroxine dosage increase140 141 142 161 160
Cardiac glycosides	Decreased serum digitalis glycoside concentrations in patients with hyperthyroidism or in patients with hypothyroidism in whom a euthyroid state has been achieved; potential for reduced therapeutic effects of digitalis glycosides with levothyroxine140 141 142 161 160	May need to increase dosage of digitalis glycoside when hypothyroidism has been corrected140 141 142 161 160
Corticosteroids (e.g., dexamethasone at dosages >4 mg daily)	Decreased metabolism of T4 to T3140 141 142 161 160 . Short-term administration of large doses of corticosteroids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels140 141 142 161 160
Ferrous sulfate	Delayed or impaired levothyroxine absorption140 141 142 161 160	Administer levothyroxine at least 4 hours apart from this agent140 141 142 154 161 160
Food with large amounts of fiber (e.g., cotton seed meal, infant soybean formula, soybean flour, walnuts)	Delayed or impaired levothyroxine absorption140 141 142 161 160
Fusosemide (at IV dosages >80 mg)	Concomitant use with levothyroxine produces transient increases in serum free T4 concentrations; continued administration results in a decrease in serum T4 and normal free T4 and TSH concentrations, and therefore, patients are clinically euthyroid140 141 142 161 160
GI drugs (e.g., antacids [aluminum hydroxide, magnesium hydroxide, calcium carbonate], simethicone, sucralfate)	Delayed or impaired levothyroxine absorption140 141 142 161 160	Administer levothyroxine at least 4 hours apart from these agents140 141 142 154 161 160
Growth hormones (e.g., somatropin)	Excessive levothyroxine use with growth hormones may accelerate epiphyseal closure; however, untreated hypothyroidism may interfere with growth response to growth hormone140 141 142 161 160