LEVOTHYROXINE SODIUM_- levothyroxine sodium_tablet

Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins. Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as endogenous T4, thereby maintaining normal T4 levels when a deficiency is present. Absorption [see Drug Interactions ( 7 Distribution [see Drug Interactions ( 7 [see Use in Specific Populations ( 8. 1 Elimination Metabolism Excretion Table 10. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency t 1/2 (days) Protein Binding (%)* Levothyroxine (T4) 10 - 20 1 6-7** 99. 96 Liothyronine 1 4 <= 2 99. 5 * Includes TBG, TBPA, and TBA ** 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism.

Hypothyroidism Limitations of Use Levothyroxine sodium tablets are not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and overtreatment with levothyroxine sodium tablets may induce hyperthyroidism [see Warnings and Precautions ( 5. 1 Levothyroxine sodium tablets are a L-thyroxine (T4) indicated in adult and pediatric patients, including neonates, for: Hypothyroidism: As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. ( 1 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. ( 1 Limitations of Use: Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast. 1 Administer at least 4 hours before or after drugs that are known to interfere with absorption. 1 Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect absorption. 1 Advise patients to stop biotin and biotin-containing supplements at least 2 days before assessing TSH and/or T4 levels. 2 Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, and concomitant medications. Peak therapeutic effect may not be attained for 4-6 weeks. 2 See full prescribing information for dosing in specific patient populations. 3 Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status. 4 Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half to one hour before breakfast. [see Drug Interactions ( 7. 1 [see Dosage and Administration ( 2. 3 [see Drug Interactions ( 7. 9 The dosage of levothyroxine sodium tablets for hypothyroidism or pituitary TSH suppression depends on a variety of factors including: the patient's age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food and the specific nature of the condition being treated [see Dosage and Administration ( 2. 3 5 7) [see Dosage and Administration ( 2. 4)] see Dosage and Administration ( 2. 3 see Dosage and Administration ( 2. 3 Inquire whether patients are taking biotin or biotin-containing supplements. If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels [ see Dosage and Administration ( 2. 10) Primary, Secondary, and Tertiary Hypothyroidism in Adults [see Dosage and Administration ( 2. Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Adults* Patient Population Starting Dosage Dosage Titration Based on Serum TSH or Free-T4 Adults diagnosed with hypothyroidism Full replacement dose is 1. 6 mcg/kg/day. Some patients require a lower starting dose. Titrate dosage by 12. 5 to 25 mcg increments every 4 to 6 weeks, as needed until the patient is euthyroid. Adults at risk for atrial fibrillation or with underlying cardiac disease Lower starting dose (less than 1. 6 mcg/kg/day) Titrate dosage every 6 to 8 weeks, as needed until the patient is euthyroid. Geriatric patients Lower starting dose (less than 1. 6 mcg/kg/day) * Dosages greater than 200 mcg/day are seldom required. An inadequate response to daily dosages greater than 300 mcg/day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors [see Dosage and Administration ( 2. 1) (7 see Dosage and Administration ( 2. Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Pediatric Patients Age Starting Daily Dosage Per Kg Body Weight* 0-3 months 10-15 mcg/kg/day 3-6 months 8-10 mcg/kg/day 6-12 months 6-8 mcg/kg/day 1-5 years 5-6 mcg/kg/day 6-12 years 4-5 mcg/kg/day Greater than 12 years but growth and 2-3 mcg/kg/day Growth and puberty complete 1. 6 mcg/kg/day * Adjust dosage based on clinical response and laboratory parameters [see Dosage and Administration ( 2. 4 and Use in Specific Populations ( 8. Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Pregnant Patients Patient Population Starting Dosage Dose Adjustment and Titration Pre-existing primary hypothyroidism with serum TSH above normal trimester-specific range Pre-pregnancy dosage may increase during pregnancy Increase levothyroxine sodium dosage by 12. 5 to 25 mcg per day. Monitor TSH every 4 weeks until a stable dose is reached and serum TSH is within normal trimester-specific range. Reduce levothyroxine sodium dosage to pre-pregnancy levels immediately after delivery. Monitor serum TSH 4 to 8 weeks postpartum. New onset hypothyroidism (TSH >= 10 mIU per liter) 1. 6 mcg/kg/day Monitor serum TSH every 4 weeks and adjust levothyroxine sodium dosage until serum TSH is within normal trimester-specific range. New onset hypothyroidism (TSH < 10 mIU per liter) 1. 0 mcg/kg/day TSH Suppression in Well-differentiated Thyroid Cancer in Adult and Pediatric Patients Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. Biotin supplementation may interfere with immunoassays for TSH, T4, and T3, resulting in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days before assessing TSH and/or T4 levels [see Drug Interactions ( 7. 10 Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of levothyroxine sodium may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors. Adults Pediatric Patients [see Warnings and Precautions ( 5. 4 Secondary and Tertiary Hypothyroidism.

Adverse reactions associated with levothyroxine sodium therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions ( 5 10 General: Central nervous system: Musculoskeletal: Cardiovascular: Respiratory: Gastrointestinal: Dermatologic: Endocrine: Reproductive: Adverse Reactions in Pediatric Patients Hypersensitivity Reactions Adverse reactions associated with levothyroxine sodium therapy are primarily those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, muscle spasm, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
Thyroid hormones, including levothyroxine sodium, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. [see Adverse Reactions ( 6 7. 7 10 WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS See full prescribing information for complete boxed warning. Thyroid hormones, including levothyroxine sodium, should not be used for the treatment of obesity or for weight loss. Doses beyond the range of daily hormonal requirements may produce serious or even life-threatening manifestations of toxicity ( 6 10.
CONTRAINDICATIONS
Levothyroxine sodium tablets are contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions ( 5. 4 Uncorrected adrenal insufficiency.

Pregnancy may require the use of higher doses of levothyroxine sodium. 1 Risk Summary (see Clinical Considerations) Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Dose Adjustments During Pregnancy and the Postpartum Period [see Dosage and Administration ( 2. 3 Risk Summary Levothyroxine sodium is indicated in patients from birth to less than 17 years of age: As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. [see Warnings and Precautions ( 5. 1 Because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium at less than the full replacement dose [see Dosage and Administration ( 2.

See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e. , absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium. ( 7 Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e. , absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium (Tables 5 to 8). Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Phosphate Binders Phosphate binders may bind to levothyroxine. Administer levothyroxine sodium tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and levothyroxine sodium for changes in thyroid function. Bile Acid Sequestrants Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels. Proton Pump Inhibitors Sucralfate Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class Effect Clofibrate These drugs may increase serum thyroxine-binding globulin (TBG) concentration. Androgens / Anabolic These drugs may decrease serum TBG concentration. Potential impact (below): Administration of these agents with levothyroxine sodium results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine sodium requirements. Drug or Drug Class Effect Phenobarbital Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. Drugs That May Decrease Conversion of T4 to T3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class Effect Beta-adrenergic antagonists In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. Glucocorticoids Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). Other drugs: Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients. Addition of levothyroxine sodium therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued [see Warnings and Precautions ( 5. 5 Levothyroxine sodium increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the levothyroxine sodium dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. Levothyroxine sodium may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. Concurrent use of tricyclic (e. , amitriptyline) or tetracyclic (e. , maprotiline) antidepressants and levothyroxine sodium may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. Levothyroxine sodium may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium may result in increased levothyroxine sodium requirements. Concurrent use of ketamine and levothyroxine sodium may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. Concurrent use of sympathomimetics and levothyroxine sodium may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients. Consumption of certain foods may affect levothyroxine sodium absorption thereby necessitating adjustments in dosing [see Dosage and Administration ( 2. 1 Thyroxine-binding Globulin (TBG) Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.

OVERDOSAGE
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions ( 5 6
NONCLINICAL TOXICOLOGY
Long-term carcinogenicity studies in animals to evaluate the carcinogenic potential of levothyroxine have not been performed. Studies to evaluate mutagenic potential and animal fertility have not been performed.

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