Levothyroxine Sodium

LEVOTHROID® (levothyroxine sodium) Tablets, USP contains synthetic crystalline L-3, 3', 5, 5'-tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is identical to that produced in the human thyroid gland. Levothyroxine (T4) sodium has an empirical formula of C15H10I4N NaO4 x H2O, molecular weight of 798. 86 g/mol (anhydrous), and structural formula as shown:

Inactive Ingredients: Microcrystalline cellulose, calcium phosphate dibasic, povidone and magnesium stearate. The following are the coloring additives per tablet strength.

Levothyroxine sodium is used for the following indications:

Hypothyroidism

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 and subclinical hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.

Pituitary TSH Suppression

In the treatment or prevention of various types of euthyroid goiters (see WARNINGS and PRECAUTIONS), including thyroid nodules (see WARNINGS and PRECAUTIONS), subacute or chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter (see WARNINGS and PRECAUTIONS) and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

WARNING

Thyroid hormones, including LEVOXYL, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

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

In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS). If the serum TSH level is not suppressed, LEVOXYL should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.

Levothyroxine is a replacement for a hormone that is normally produced by your thyroid gland to regulate the body's energy and metabolism. Levothyroxine is given when the thyroid does not produce enough of this hormone on its own.

Levothyroxine treats hypothyroidism (low thyroid hormone). Levothyroxine is also used to treat or prevent goiter (enlarged thyroid gland), which can be caused by hormone imbalances, radiation treatment, surgery, or cancer.

Levothyroxine should not be used to treat obesity or weight problems.

Levothyroxine may also be used for purposes not listed in this medication guide.

Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage. They include the following:

General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating;

Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia;

Musculoskeletal: tremors, muscle weakness;

Cardiac: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest;

Pulmonary: dyspnea;

GI: diarrhea, vomiting, abdominal cramps;

Dermatologic: hair loss, flushing;

Reproductive: menstrual irregularities, impaired fertility.

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.

Seizures have been reported rarely with the institution of levothyroxine therapy.

Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism.

Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

In addition to the above events, the following have been reported, predominately when Levoxyl tablets were not taken with water: choking, gagging, tablet stuck in throat and dysphagia (see PATIENT INFORMATION).

Read the entire FDA prescribing information for Levoxyl (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.140 141 142 143 160 Specific indications include subclinical hypothyroidism and primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism.140 141 142 143 160

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

Used IV for treatment of myxedema coma.155 165

Has been used IV in other conditions when rapid thyroid replacement is required†;161 however, this is not an FDA-labeled use for the currently available injection.165

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.140 141 142 160

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

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

Other Uses

See Unlabeled Uses under Cautions.

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 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 injection.140 141 142 143 160 165 The drug also has been administered by IM injection†;161 however, IV is preferred 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.

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.165 Resultant solutions contain approximately 20, 40, or 100 mcg/mL, respectively.a 165

Use reconstituted solutions immediately and discard any unused portions; do not admix with IV infusion solutions.165 (See Powder for Injection under Stability.)

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.140 141 142 160 (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

Use caution when switching patients from oral to IV administration; relative bioavailability and accurate dosing conversion between oral and IV preparations not established.165

Pediatric Patients

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:

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.140 141 142 160 (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

Adults

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

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.165

Initial loading dose is 300–500 mcg;165 some clinicians recommend an initial dose of 100–500 mcg.155

Maintenance dosage: 50–100 mcg daily as clinically indicated until patient’s condition stabilizes and drug can be given orally.165

Use caution when switching patients from oral to IV levothyroxine; relative bioavailability and accurate dosing conversion between oral and IV preparations not established.165

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

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

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

Oral: Initiate therapy at lower doses than those recommended in patients without cardiovascular disease.140 141 142 160 For patients <50 years of age with underlying cardiovascular disease, usual initial dosage is 25–50 mcg once daily;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.140 141 142 160

IV: Excessive bolus doses >500 mcg associated with cardiac complications, particularly in patients with underlying cardiac conditions.165

Cautious use (e.g., smaller IV doses) may be warranted.165

Geriatric Patients

Oral: Initiate therapy at lower doses than those recommended in younger patients.140 141 142 160

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

IV: Excessive bolus doses >500 mcg associated with cardiac complications.165

Cautious use (e.g., smaller IV doses) may be warranted.155 165

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.141 142 160 165

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.140 141 142 160 165 However, serum T4 concentrations usually remain within normal range but may occasionally be slightly increased.140 141 142 160 165

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.140 141 142 160 165 Consult specialized references for information.

Some drugs may affect transport of thyroid hormones (T3, T4, levothyroxine) by affecting serum thyroxine-binding globulin (TBG) concentrations.140 141 142 160 165 However, free T4 concentrations may remain normal and the patient may remain euthyroid.140 141 142 160 Monitor therapy and adjust levothyroxine dosages as necessary.140 141 142 160

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)

Absorption

Bioavailability

Variably absorbed from the GI tract (range: 40–80%).137 140 141 142 143 159 160

Extent of absorption is increased in the fasting state and decreased in malabsorption states (e.g., sprue); absorption also may decrease with age.140 141 142 140 141 142

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%.165

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).144

Onset

Due to the long half-life, peak therapeutic effects may not be attained for 4–6 weeks.140 141 142 160

Food

Infant soybean formula, soybean flour, cotton seed meal, walnuts, and foods containing large amounts of fiber may decrease absorption of levothyroxine.139 140 141 142

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.140 141 142 160 165

Minimally distributed into breast milk.140 141 142 160

Plasma Protein Binding

Circulating thyroid hormones are >99% bound to plasma proteins, including TBG, thyroxine-binding prealbumin (TBPA), and albumin.140 141 142 160 165 Only unbound hormone is metabolically active.140 141 142 160 165

Elimination

Metabolism

T4 and T3 are metabolized principally in the liver through sequential deiodination.140 141 142 160 165 Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3).140 141 142 160 165 T3 and rT3 are further deiodinated to diiodothyronine.140 141 142 160 165 Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.140 141 142 160 165

Elimination Route

Primarily eliminated by the kidneys.140 141 142 160 165 A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces.140 141 142 160 165 Approximately 20% of T4 is eliminated in the stool.140 141 142 160 Urinary excretion of T4 decreases with age.140 141 142 160 165

Half-life

6–8 days for T4 (3–4 days in hyperthyroidism; 9–10 days in hypothyroidism).140 141 142 160 165

≤ 2 days for T3.140 141 142 160 165

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