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FDA Drug information

Levothyroxine Sodium

Read time: 6 mins
Marketing start date: 27 May 2024

Summary of product characteristics


Adverse Reactions

6 ADVERSE REACTIONS Adverse reactions associated with levothyroxine sodium therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5) , Overdosage (10) ] . 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, muscle spasm Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest Respiratory: dyspnea Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests Dermatologic: hair loss, flushing, rash Endocrine: decreased bone mineral density Reproductive: menstrual irregularities, impaired fertility Seizures have been reported rarely with the institution of levothyroxine therapy. Adverse Reactions in Pediatric Patients Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants who have not undergone complete closure of the fontanelles, and in premature closure of the epiphyses in pediatric patients still experiencing growth with resultant compromised adult height. Hypersensitivity Reactions Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur. 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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Contraindications

4 CONTRAINDICATIONS Levothyroxine sodium is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (5.4) ] . Uncorrected adrenal insufficiency. (4)

Description

11 DESCRIPTION Levothyroxine sodium tablets, USP contain synthetic crystalline L-3,3',5,5'-tetraiodothyronine sodium salt [levothyroxine (T 4 ) sodium]. Synthetic T 4 is chemically identical to that produced in the human thyroid gland. Levothyroxine (T 4 ) sodium has an empirical formula of C 15 H 10 I 4 N NaO 4 • H 2 O, molecular weight of 798.86 (anhydrous), and structural formula as shown: Levothyroxine sodium tablets, USP for oral administration are supplied in the following strengths: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, and 300 mcg. Each levothyroxine sodium tablet, USP contains the inactive ingredients acacia, croscarmellose sodium, lactose monohydrate, magnesium stearate, sucrose, and vitamin E. Table 9 provides a listing of the color additives by tablet strength: Table 9. Levothyroxine Sodium Tablets, USP Color Additives Strength (mcg) Color additive(s) 25 FD&C Yellow No. 6 Aluminum Lake a 50 None 75 FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake 88 D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1, Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake a 100 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake a 112 D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake 125 FD&C Yellow No. 6 Aluminum Lake a , FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake 137 FD&C Blue No. 1 Aluminum Lake 150 FD&C Blue No. 2 Aluminum Lake 175 D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake 200 FD&C Red No. 40 Aluminum Lake 300 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake a , FD&C Blue No. 1 Aluminum Lake * Note – FD&C Yellow No. 6 is orange in color. FDA approved dissolution test specifications differ from USP. Structural Formula

Dosage And Administration

2 DOSAGE AND ADMINISTRATION Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast. (2.1) Administer at least 4 hours before or after drugs that are known to interfere with absorption. (2.1) Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect absorption. (2.1) 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 to 6 weeks. (2.2) See full prescribing information for dosing in specific patient populations. (2.3) Adequacy of therapy determined with periodic monitoring of TSH and/or T 4 as well as clinical status. (2.4) 2.1 Important Administration Instructions Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half to one hour before breakfast. Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere with levothyroxine sodium tablets absorption [see Drug Interactions (7.1) ] . Evaluate the need for dosage adjustments when regularly administering within one hour of certain foods that may affect levothyroxine sodium tablets absorption [see Dosage and Administration (2.2 and 2.3 ), Drug Interactions (7.9) and Clinical Pharmacology (12.3) ] . Administer levothyroxine sodium tablets to pediatric patients who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL) of water and immediately administering the suspension by spoon or dropper. Ensure the patient ingests the full amount of the suspension. Do not store the suspension. Do not administer in foods that decrease absorption of levothyroxine sodium tablets, such as soybean-based infant formula [see Drug Interactions (7.9) ] . 2.2 Important Considerations for Dosing 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) , Warnings and Precautions (5) , and Drug Interactions (7) ] . Dosing must be individualized to account for these factors and dosage adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.4) ] . For adult patients with primary hypothyroidism, titrate until the patient is clinically euthyroid and the serum TSH returns to normal [see Dosage and Administration (2.3) ] . For secondary or tertiary hypothyroidism, serum TSH is not a reliable measure of levothyroxine sodium dosage adequacy and should not be used to monitor therapy. Use the serum free-T4 level to titrate levothyroxine sodium dosing until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range [see Dosage and Administration (2.3) ] . The peak therapeutic effect of a given dose of levothyroxine sodium tablets may not be attained for 4 to 6 weeks. 2.3 Recommended Dosage and Titration Primary, Secondary, and Tertiary Hypothyroidism in Adults The recommended starting daily dosage of levothyroxine sodium tablets in adults with primary, secondary, or tertiary hypothyroidism is based on age and comorbid cardiac conditions, as described in Table 1. For patients at risk of atrial fibrillation or patients with underlying cardiac disease, start with a lower dosage and titrate the dosage more slowly to avoid exacerbation of cardiac symptoms. Dosage titration is based on serum TSH or free-T4 [see Dosage and Administration (2.2) ] . Table 1. 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) and Drug Interactions (7) ] . Primary, Secondary, and Tertiary Hypothyroidism in Pediatric Patients The recommended starting daily dosage of levothyroxine sodium tablets in pediatric patients with primary, secondary, or tertiary hypothyroidism is based on body weight and changes with age as described in Table 2. Titrate the dosage (every 2 weeks) as needed based on serum TSH or free-T4 until the patient is euthyroid [see Dosage and Administratio n (2.2) ] . Table 2. Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Pediatric Patients Age Starting Daily Dosage Per Kg Body Weight * 0 to 3 months 10 to 15 mcg/kg/day 3 to 6 months 8 to 10 mcg/kg/day 6 to 12 months 6 to 8 mcg/kg/day 1 to 5 years 5 to 6 mcg/kg/day 6 to 12 years 4 to 5 mcg/kg/day Greater than 12 years but growth and puberty incomplete 2 to 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 (8.4) ] . Pediatric Patients from Birth to 3 Months of Age at Risk for Cardiac Failure Start at a lower starting dosage and increase the dosage every 4 to 6 weeks as needed based on clinical and laboratory response. Pediatric Patients at Risk for Hyperactivity To minimize the risk of hyperactivity, start at one-fourth the recommended full replacement dosage, and increase on a weekly basis by one-fourth the full recommended replacement dosage until the full recommended replacement dosage is reached. Hypothyroidism in Pregnant Patients For pregnant patients with pre-existing hypothyroidism, measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy. In pregnant patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. The recommended daily dosage of levothyroxine sodium tablets in pregnant patients is described in Table 3. Table 3. 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 tablets 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 tablets dosage to pre-pregnancy levels immediately after delivery. Monitor serum TSH 4 to 8 weeks postpartum. New onset hypothyroidism (TSH ≥ 10 IU per liter) 1.6 mcg/kg/day Monitor serum TSH every 4 weeks and adjust levothyroxine sodium tablets dosage until serum TSH is within normal trimester-specific range. New onset hypothyroidism (TSH < 10 IU per liter) 1.0 mcg/kg/day TSH Suppression in Well-differentiated Thyroid Cancer in Adult and Pediatric Patients The levothyroxine sodium tablets dosage is based on the target level of TSH suppression for the stage and clinical status of thyroid cancer. 2.4 Monitoring TSH and/or Thyroxine (T 4 ) Levels Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of levothyroxine sodium tablets may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors. Adults In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8 weeks after any change in dosage. In patients on a stable and appropriate replacement dosage, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient’s clinical status. Pediatric Patients In patients with hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T 4 . Monitor TSH and total or free-T 4 in pediatric patients as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dosage stabilization until growth is completed. Poor compliance or abnormal values may necessitate more frequent monitoring. Perform routine clinical examination, including assessment of development, mental and physical growth, and bone maturation, at regular intervals. The general aim of therapy is to normalize the serum TSH level. TSH may not normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. Failure of the serum T 4 to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium tablets therapy and/or of the serum TSH to decrease below 20 IU per liter within 4 weeks may indicate the patient is not receiving adequate therapy. Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of levothyroxine sodium tablets [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] . Secondary and Tertiary Hypothyroidism Monitor serum free-T 4 levels and maintain in the upper half of the normal range in these patients.

Indications And Usage

1 INDICATIONS AND USAGE Hypothyroidism Levothyroxine sodium tablets are indicated in adult and pediatric patients, including neonates, as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression Levothyroxine sodium tablets are indicated in adult and pediatric patients, including neonates, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. 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 not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. Levothyroxine sodium tablets are a L-thyroxine (T 4 ) 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.

Overdosage

10 OVERDOSAGE The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6) ] . In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Reduce the levothyroxine sodium dosage or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s medical status. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

Drug Interactions

7 DRUG INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium. (7) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium (Tables 5 to 8). Table 5. Drugs That May Decrease T 4 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 (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum) Phosphate binders may bind to levothyroxine. Administer levothyroxine sodium 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 (e.g., colesevelam, cholestyramine, colestipol) Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium at least 4 hours prior to these drugs or monitor TSH levels. Ion Exchange Resins (e.g., Kayexalate) Proton Pump Inhibitors 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. Sucralfate Antacids (e.g., aluminum & magnesium hydroxides, simethicone) Table 6. Drugs That May Alter T 4 and Triiodothyronine (T 3 ) Serum Transport Without Affecting Free Thyroxine (FT 4 ) Concentration (Euthyroidism) Drug or Drug Class Effect Clofibrate These drugs may increase serum thyroxine-binding globulin (TBG) concentration. Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids These drugs may decrease serum TBG concentration. Asparaginase Glucocorticoids Slow-Release Nicotinic Acid Potential impact (below): Administration of these agents with levothyroxine sodium results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations. Salicylates (> 2 g/day) Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T 4 levels may decrease by as much as 30%. Other drugs: These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T 4 to TBG and albumin, causing an increase free T 4 fraction in serum. Furosemide competes for T 4 -binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T 4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. Carbamazepine Furosemide (> 80 mg Intravenous) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates Table 7. Drugs That May Alter Hepatic Metabolism of T 4 (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 T 4 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. Rifampin Table 8. Drugs That May Decrease Conversion of T 4 to T 3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3 , leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class Effect Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day) In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 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 (e.g., Dexamethasone ≥ 4 mg/day) Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (See above). Other drugs: Amiodarone inhibits peripheral conversion of levothyroxine (T 4 ) to triiodothyronine (T 3 ) and may cause isolated biochemical changes (increase in serum free-T 4 , and decreased or normal free-T 3 ) in clinically euthyroid patients. Amiodarone 7.2 Antidiabetic Therapy 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) ] . 7.3 Oral Anticoagulants 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. 7.4 Digitalis Glycosides 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. 7.5 Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., 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. 7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics 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. 7.8 Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients. 7.9 Drug-Food Interactions Consumption of certain foods may affect levothyroxine sodium absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1) ] . Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. 7.10 Drug-Laboratory Test Interactions Consider changes in TBG concentration when interpreting T 4 and T 3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T 4 index (FT 4 I) 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 9,000.

Drug Interactions Table

Table 5. 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

(e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum)

Phosphate binders may bind to levothyroxine. Administer levothyroxine sodium 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

(e.g., colesevelam, cholestyramine, colestipol)

Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium at least 4 hours prior to these drugs or monitor TSH levels.

Ion Exchange Resins

(e.g., Kayexalate)

Proton Pump Inhibitors

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.

Sucralfate

Antacids

(e.g., aluminum & magnesium hydroxides, simethicone)

Clinical Pharmacology

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T 3 ) and L-thyroxine (T 4 ) 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. The physiological actions of thyroid hormones are produced predominantly by T 3 , the majority of which (approximately 80%) is derived from T 4 by deiodination in peripheral tissues. 12.2 Pharmacodynamics Oral levothyroxine sodium is a synthetic T 4 hormone that exerts the same physiologic effect as endogenous T 4 , thereby maintaining normal T 4 levels when a deficiency is present. 12.3 Pharmacokinetics Absorption Absorption of orally administered T 4 from the gastrointestinal tract ranges from 40% to 80%. The majority of the levothyroxine sodium dose is absorbed from the jejunum and upper ileum. The relative bioavailability of levothyroxine sodium tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T 4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T 4 . Absorption may also decrease with age. In addition, many drugs and foods affect T 4 absorption [see Drug Interactions (7 ) ] . Distribution Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T 4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T 4 compared to T 3 . Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins [see Drug Interactions (7) ] . Thyroid hormones do not readily cross the placental barrier [see Use in Specific Populations (8.1 ) ] . Elimination Metabolism T 4 is slowly eliminated (see Table 10). The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T 3 is derived from peripheral T 4 by monodeiodination. The liver is the major site of degradation for both T 4 and T 3 , with T 4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T 4 is deiodinated to yield equal amounts of T 3 and reverse T 3 (rT 3 ). T 3 and rT 3 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. Excretion Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T 4 is eliminated in the stool. Urinary excretion of T 4 decreases with age. Table 10. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency t 1/2 (days) Protein Binding (%) * Levothyroxine (T 4 ) 10 to 20 1 6 to 7** 99.96 Liothyronine (T 3 ) 1 4 ≤ 2 99.5 * Includes TBG, TBPA, and TBA ** 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism

Clinical Pharmacology Table

Table 10. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone

Ratio in Thyroglobulin

Biologic Potency

t1/2 (days)

Protein Binding (%)*

Levothyroxine (T4)

10 to 20

1

6 to 7**

99.96

Liothyronine (T3)

1

4

≤ 2

99.5

* Includes TBG, TBPA, and TBA

** 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism

Mechanism Of Action

12.1 Mechanism of Action Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T 3 ) and L-thyroxine (T 4 ) 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. The physiological actions of thyroid hormones are produced predominantly by T 3 , the majority of which (approximately 80%) is derived from T 4 by deiodination in peripheral tissues.

Pharmacodynamics

12.2 Pharmacodynamics Oral levothyroxine sodium is a synthetic T 4 hormone that exerts the same physiologic effect as endogenous T 4 , thereby maintaining normal T 4 levels when a deficiency is present.

Pharmacokinetics

12.3 Pharmacokinetics Absorption Absorption of orally administered T 4 from the gastrointestinal tract ranges from 40% to 80%. The majority of the levothyroxine sodium dose is absorbed from the jejunum and upper ileum. The relative bioavailability of levothyroxine sodium tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T 4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T 4 . Absorption may also decrease with age. In addition, many drugs and foods affect T 4 absorption [see Drug Interactions (7 ) ] . Distribution Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T 4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T 4 compared to T 3 . Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins [see Drug Interactions (7) ] . Thyroid hormones do not readily cross the placental barrier [see Use in Specific Populations (8.1 ) ] . Elimination Metabolism T 4 is slowly eliminated (see Table 10). The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T 3 is derived from peripheral T 4 by monodeiodination. The liver is the major site of degradation for both T 4 and T 3 , with T 4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T 4 is deiodinated to yield equal amounts of T 3 and reverse T 3 (rT 3 ). T 3 and rT 3 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. Excretion Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T 4 is eliminated in the stool. Urinary excretion of T 4 decreases with age. Table 10. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency t 1/2 (days) Protein Binding (%) * Levothyroxine (T 4 ) 10 to 20 1 6 to 7** 99.96 Liothyronine (T 3 ) 1 4 ≤ 2 99.5 * Includes TBG, TBPA, and TBA ** 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism

Pharmacokinetics Table

Table 10. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone

Ratio in Thyroglobulin

Biologic Potency

t1/2 (days)

Protein Binding (%)*

Levothyroxine (T4)

10 to 20

1

6 to 7**

99.96

Liothyronine (T3)

1

4

≤ 2

99.5

* Includes TBG, TBPA, and TBA

** 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism

Effective Time

20230901

Version

11

Description Table

Table 9. Levothyroxine Sodium Tablets, USP Color Additives

Strength (mcg)

Color additive(s)

25

FD&C Yellow No. 6 Aluminum Lakea

50

None

75

FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake

88

D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1, Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lakea

100

D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lakea

112

D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake

125

FD&C Yellow No. 6 Aluminum Lakea, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake

137

FD&C Blue No. 1 Aluminum Lake

150

FD&C Blue No. 2 Aluminum Lake

175

D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake

200

FD&C Red No. 40 Aluminum Lake

300

D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lakea, FD&C Blue No. 1 Aluminum Lake

* Note – FD&C Yellow No. 6 is orange in color.

Dosage And Administration Table

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) and Drug Interactions (7)].

Dosage Forms And Strengths

3 DOSAGE FORMS AND STRENGTHS Levothyroxine sodium tablets, USP are available as follows (Table 4): Table 4: Levothyroxine Sodium Tablet Strengths and Identifying Features Tablet Strength Tablet Color/Shape Tablet Markings 25 mcg Orange/Capsule Shaped “A” bisect “N” on one side and “L” bisect “1” on the other side 50 mcg White to Off-White/Capsule Shaped “A” bisect “N” on one side and “L” bisect “2” on the other side 75 mcg Violet/Capsule Shaped “A” bisect “N” on one side and “L” bisect “3” on the other side 88 mcg Olive/Capsule Shaped “A” bisect “N” on one side and “L” bisect “4” on the other side 100 mcg Yellow/Capsule Shaped “A” bisect “N” on one side and “L” bisect “5” on the other side 112 mcg Dark Pink/Capsule Shaped “A” bisect “N” on one side and “L” bisect “6” on the other side 125 mcg Brown/Capsule Shaped “A” bisect “N” on one side and “L” bisect “7” on the other side 137 mcg Turquoise/Capsule Shaped “A” bisect “N” on one side and “L” bisect “8” on the other side 150 mcg Blue/Capsule Shaped “A” bisect “N” on one side and “L” bisect “9” on the other side 175 mcg Lilac/Capsule Shaped “A” bisect “N” on one side and “L” bisect “10” on the other side 200 mcg Pink/Capsule Shaped “A” bisect “N” on one side and “L” bisect “11” on the other side 300 mcg Green/Capsule Shaped “A” bisect “N” on one side and “L” bisect “12” on the other side Tablets: 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 mcg (3)

Dosage Forms And Strengths Table

Tablet Strength

Tablet Color/Shape

Tablet Markings

25 mcg

Orange/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “1” on the other side

50 mcg

White to Off-White/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “2” on the other side

75 mcg

Violet/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “3” on the other side

88 mcg

Olive/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “4” on the other side

100 mcg

Yellow/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “5” on the other side

112 mcg

Dark Pink/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “6” on the other side

125 mcg

Brown/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “7” on the other side

137 mcg

Turquoise/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “8” on the other side

150 mcg

Blue/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “9” on the other side

175 mcg

Lilac/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “10” on the other side

200 mcg

Pink/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “11” on the other side

300 mcg

Green/Capsule Shaped

“A” bisect “N” on one side and “L” bisect “12” on the other side

Spl Product Data Elements

Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C YELLOW NO. 6 ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C BLUE NO. 2 Olive AN;L4 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C YELLOW NO. 6 AN;L1 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL white to off-white AN;L2 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS FD&C BLUE NO. 2 FD&C RED NO. 40 ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL Violet AN;L3 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS D&C YELLOW NO. 10 ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C YELLOW NO. 6 AN;L5 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL D&C RED NO. 27 D&C RED NO. 30 dark pink AN;L6 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C YELLOW NO. 6 FD&C RED NO. 40 FD&C BLUE NO. 2 AN;L7 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C BLUE NO. 1 turquoise AN;L8 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C BLUE NO. 2 AN;L9 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS D&C RED NO. 27 D&C RED NO. 30 ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C BLUE NO. 1 lilac AN;L10 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL FD&C RED NO. 40 AN;L11 Levothyroxine Sodium Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ANHYDROUS ACACIA CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE SUCROSE ALPHA-TOCOPHEROL D&C YELLOW NO. 10 FD&C YELLOW NO. 6 FD&C BLUE NO. 1 AN;L12

Carcinogenesis And Mutagenesis And Impairment Of Fertility

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

Application Number

ANDA210831

Brand Name

Levothyroxine Sodium

Generic Name

Levothyroxine Sodium

Product Ndc

69238-1275

Product Type

HUMAN PRESCRIPTION DRUG

Route

ORAL

Package Label Principal Display Panel

PRINCIPAL DISPLAY PANEL 25mcg 100ct Label 50 mcg 100ct Label 75mcg 100ct Label 88mcg 100ct Label 100mcg 100ct Label 112mcg 100ct Label 125mcg 100ct Label 137mcg 100ct Label 150mcg 100ct Label 175mcg 100ct Label 200mcg 100ct Label 300mcg 100ct Label

Information For Patients

17 PATIENT COUNSELING INFORMATION Inform the patient of the following information to aid in the safe and effective use of levothyroxine sodium: Dosing and Administration Instruct patients to take levothyroxine sodium only as directed by their healthcare provider. Instruct patients to take levothyroxine sodium as a single dose, preferably on an empty stomach, one-half to one hour before breakfast. Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine. Instruct patients not to take levothyroxine sodium tablets within 4 hours of these agents. Instruct patients to notify their healthcare provider if they are pregnant or breastfeeding or are thinking of becoming pregnant while taking levothyroxine sodium. Important Information Inform patients that it may take several weeks before they notice an improvement in symptoms. Inform patients that the levothyroxine in levothyroxine sodium is intended to replace a hormone that is normally produced by the thyroid gland. Generally, replacement therapy is to be taken for life. Inform patients that levothyroxine sodium should not be used as a primary or adjunctive therapy in a weight control program. Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations. Instruct patients to notify their physician of any other medical conditions they may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking levothyroxine sodium. If they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. If patients are taking anticoagulants, their clotting status should be checked frequently. Instruct patients to notify their physician or dentist that they are taking levothyroxine sodium prior to any surgery. Adverse Reactions Instruct patients to notify their healthcare provider if they experience any of the following symptoms: 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. Inform patients that partial hair loss may occur rarely during the first few months of levothyroxine sodium therapy, but this is usually temporary. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 09-2023-02

Geriatric Use

8.5 Geriatric Use 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 (2.3) and Warnings and Precautions (5.2) ] . Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

Pediatric Use

8.4 Pediatric Use 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. Rapid restoration of normal serum T 4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation. Therefore, initiate levothyroxine sodium therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients [see Warnings and Precautio ns (5.1) ] . Closely monitor infants during the first 2 weeks of levothyroxine sodium therapy for cardiac overload and arrhythmias.

Pregnancy

8.1 Pregnancy Risk Summary The clinical experience, including data from post-marketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine sodium dosage adjusted during pregnancy [see Clinical Considerations] . Animal reproductive studies have not been conducted with levothyroxine sodium. Levothyroxine sodium should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development. Dose Adjustments During Pregnancy and the Postpartum Period Pregnancy may increase levothyroxine sodium requirements. Serum TSH levels should be monitored and the levothyroxine sodium dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the levothyroxine sodium dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3) ] .

Use In Specific Populations

8 USE IN SPECIFIC POPULATIONS Pregnancy may require the use of higher doses of levothyroxine sodium. (2.3, 8.1) 8.1 Pregnancy Risk Summary The clinical experience, including data from post-marketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine sodium dosage adjusted during pregnancy [see Clinical Considerations] . Animal reproductive studies have not been conducted with levothyroxine sodium. Levothyroxine sodium should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development. Dose Adjustments During Pregnancy and the Postpartum Period Pregnancy may increase levothyroxine sodium requirements. Serum TSH levels should be monitored and the levothyroxine sodium dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the levothyroxine sodium dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3) ] . 8.2 Lactation Risk Summary Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported and there is no information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levothyroxine sodium and any potential adverse effects on the breastfed infant from levothyroxine sodium or from the underlying maternal condition. 8.4 Pediatric Use 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. Rapid restoration of normal serum T 4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation. Therefore, initiate levothyroxine sodium therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients [see Warnings and Precautio ns (5.1) ] . Closely monitor infants during the first 2 weeks of levothyroxine sodium therapy for cardiac overload and arrhythmias. 8.5 Geriatric Use 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 (2.3) and Warnings and Precautions (5.2) ] . Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Levothyroxine sodium tablets, USP, 25 mcg, are supplied as orange, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “1” on the other side. They are available as follows: Bottles of 100: NDC 69238-1163-1 Levothyroxine sodium tablets, USP, 50 mcg, are supplied as white to off-white, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “2” on the other side. They are available as follows: Bottles of 100: NDC 69238-1164-1 Levothyroxine sodium tablets, USP, 75 mcg, are supplied as violet, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “3” on the other side. They are available as follows: Bottles of 100: NDC 69238-1168-1 Levothyroxine sodium tablets, USP, 88 mcg, are supplied as olive, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “4” on the other side. They are available as follows: Bottles of 100: NDC 69238-1169-1 Levothyroxine sodium tablets, USP, 100 mcg, are supplied as yellow, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “5” on the other side. They are available as follows: Bottles of 100: NDC 69238-1177-1 Levothyroxine sodium tablets, USP, 112 mcg, are supplied as dark pink, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “6” on the other side. They are available as follows: Bottles of 100: NDC 69238-1178-1 Levothyroxine sodium tablets, USP, 125 mcg, are supplied as brown, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “7” on the other side. They are available as follows: Bottles of 100: NDC 69238-1183-1 Levothyroxine sodium tablets, USP, 137 mcg, are supplied as turquoise, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “8” on the other side. They are available as follows: Bottles of 100: NDC 69238-1275-1 Levothyroxine sodium tablets, USP, 150 mcg, are supplied as blue, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “9” on the other side. They are available as follows: Bottles of 100: NDC 69238-1276-1 Levothyroxine sodium tablets, USP, 175 mcg, are supplied as lilac, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “10” on the other side. They are available as follows: Bottles of 100: NDC 69238-1277-1 Levothyroxine sodium tablets, USP, 200 mcg, are supplied as pink, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “11” on the other side. They are available as follows: Bottles of 100: NDC 69238-1278-1 Levothyroxine sodium tablets, USP, 300 mcg, are supplied as green, capsule shaped, flat faced beveled edge tablets, scored on both sides, debossed with “A” bisect “N” on one side and “L” bisect “12” on the other side. They are available as follows: Bottles of 100: NDC 69238-1279-1 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Levothyroxine sodium tablets, USP should be protected from light and moisture.

Boxed Warning

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. 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 [see Adverse Reactions (6) , Drug Interactions (7.7) , and Overdosage (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 ).

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