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 or other conditions when rapid thyroid replacement is required.
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.
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). 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. Check Orange Book at http://www.fda.gov/cder/ob 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 or IM injection. IV is preferred over IM 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 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. Resultant solutions contain approximately 40 or 100 mcg/mL, respectively.
Alternatively, to produce Synthroid® solutions containing approximately 100 mcg/mL, add 2 mL 0.9% sodium chloride injection to vial containing 200 mcg.
Use reconstituted solutions immediately and discard any unused portions; do not admix with IV infusion solutions.
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.
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:
Dosage for Management of Hypothyroidism in Pediatric Patients
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.
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.
IV or IM
Replacement therapy: initially about one-half previously established oral dosage. Monitor patients closely and adjust dosage according to patient’s tolerance and therapeutic response.
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.
IV and IM
Replacement therapy: about one-half previously established oral dosage. Usual parenteral maintenance dosage is 50–100 mcg daily.
Monitor patients closely and adjust dosage according to patient’s tolerance and therapeutic response.
Myxedema Coma
IV
In patients who do not have severe cardiovascular disease, usual initial dose is 200–500 mcg; some clinicians recommend an initial dose of 100–500 mcg. If substantial and progressive improvements have not been achieved, administer 100–300 mcg or greater IV on the second day. Lower daily IV dosages should then be administered as needed until patient’s condition stabilizes and drug can be given orally.
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
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 daily given as a single dose; 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
If levothyroxine therapy is clinically indicated, smaller initial IV doses may be necessary. Consider risks of adverse cardiovascular effects associated with sudden IV administration of large doses of levothyroxine sodium against risks of withholding therapy.
Geriatric Patients
Hypothyroidism
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
Reduced initial dose may be appropriate in geriatric patients.
Cautions
Contraindications
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.)
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).
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.
Associated Endocrine Disorders
In patients with secondary or tertiary hypothyroidism, consider possibility of additional hypothalamic/pituitary hormone deficiencies and treat if diagnosed.
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.
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 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
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.
Geriatric Use
Because of the increased risk of cardiovascular disease among geriatric patients, levothyroxine therapy should not be initiated at the full replacement dose.
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.
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.
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 levothyroxine
May need to increase dosage of digitalis glycoside when hypothyroidism has been corrected
Corticosteroids (e.g., dexamethasone at dosages >4 mg daily)
Decreased metabolism of T4 to T3. Short-term administration of large doses of corticosteroids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels
Administer levothyroxine at least 4 hours apart from this agent
Food with large amounts of fiber (e.g., cotton seed meal, infant soybean formula, soybean flour, walnuts)
Delayed or impaired levothyroxine absorption
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 euthyroid
Excessive levothyroxine use with growth hormones may accelerate epiphyseal closure; however, untreated hypothyroidism may interfere with growth response to growth hormone
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 euthyroid
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 euthyroid
Inhibit binding of T4 and T3 to TBG and transthyretin; initially increases serum free T4 followed by return to normal concentrations with sustained therapeutic serum salicylate concentrations, although total T4 concentrations may decrease by as much as 30%
Clearance of xanthine derivatives may be decreased in hypothyroid patients but returns to normal when the euthyroid state is achieved
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.
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.
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.
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.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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