Levolet

Description

LEVOLET (levothyroxine sodium tablets, USP) contain synthetic crystalline L-3,3′,5,5’tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is chemically identical to that produced in the human thyroid gland. Levothyroxine (T4) sodium has an empirical formula of C₁₅H₁₀I₄N NaO₄• H₂O, molecular weight of 798.86 (anhydrous), and structural formula as shown:

 

LEVOLET tablets 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 LEVOLET tablet contains the inactive ingredients butylhydroxyanisole, hydroxypropyl methylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, and talc. Table 6 provides a listing of the color additives by tablet strength:

Table 6: LEVOLET Tablets Color Additives

Strength (mcg)	Color additive(s)
25	FD&C Yellow No. 6 Aluminum Lakea
50	None
75	FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake
88	FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lakea, D&C Yellow No. 10 Aluminum Lake
100	D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lakea
112	D&C Red No. 27 & 30 Aluminum Lake
125	FD&C Yellow No. 6 Aluminum Lakea, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake
137	FD&C Blue No. 1 Aluminum Lake
150	FD&C Blue No. 2 Aluminum Lake
175	FD&C Blue No. 1 Aluminum Lake, D&C Red No. 27 & 30 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
a Note – FD&C Yellow No. 6 is orange in color.

 

Hypothyroidism

LEVOLET is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

LEVOLET is indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Limitations Of Use

• LEVOLET is 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 LEVOLET may induce hyperthyroidism [see WARNINGS AND PRECAUTIONS].
• LEVOLET is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

Dosage And Administration

General Administration Information

Administer LEVOLET as a single daily dose, on an empty stomach, one-half to one hour before breakfast.

Administer LEVOLET at least 4 hours before or after drugs known to interfere with LEVOLET absorption [see DRUG INTERACTIONS].

Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect LEVOLET absorption [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Administer LEVOLET to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL or 1 to 2 teaspoons) 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 LEVOLET, such as soybean-based infant formula [see DRUG INTERACTIONS].

General Principles Of Dosing

The dose of LEVOLET 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, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS]. Dosing must be individualized to account for these factors and dose adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters [see DOSAGE AND ADMINISTRATION].

The peak therapeutic effect of a given dose of LEVOLET may not be attained for 4 to 6 weeks.

Dosing In Specific Patient Populations

Primary Hypothyroidism In Adults And In Adolescents In Whom Growth And Puberty Are Complete

Start LEVOLET at the full replacement dose in otherwise healthy, non-elderly individuals who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of LEVOLET is approximately 1.6 mcg per kg per day (for example: 100 to 125 mcg per day for a 70 kg adult).

Adjust the dose by 12.5 to 25 mcg increments every 4 to 6 weeks until the patient is clinically euthyroid and the serum TSH returns to normal. Doses greater than 200 mcg per day are seldom required. An inadequate response to daily doses of greater than 300 mcg per day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.

For elderly patients or patients with underlying cardiac disease, start with a dose of 12.5 to 25 mcg per day. Increase the dose every 6 to 8 weeks, as needed until the patient is clinically euthyroid and the serum TSH returns to normal. The full replacement dose of LEVOLET may be less than 1 mcg per kg per day in elderly patients.

In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg per day. Adjust the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the patient is clinically euthyroid and the serum TSH level is normalized.

Secondary Or Tertiary Hypothyroidism

Start LEVOLET at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of LEVOLET dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor adequacy of therapy in this patient population. Titrate LEVOLET dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

Pediatric Dosage -Congenital Or Acquired Hypothyroidism

The recommended daily dose of LEVOLET in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start LEVOLET at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0-3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response [see DOSAGE AND ADMINISTRATION].

Table 1: LEVOLET Dosing Guidelines for Pediatric Hypothyroidism

AGE	Daily Dose Per Kg Body Weighta
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 puberty incomplete	2-3 mcg/kg/day
Growth and puberty complete	1.6 mcg/kg/day
a The dose should be adjusted based on clinical response and laboratory parameters [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

 

Pediatric Patients From Birth To 3 Months Of Age At Risk For Cardiac Failure

Start at a lower starting dose and increase the dose 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 dose, and increase on a weekly basis by one-fourth the full recommended replacement dose until the full recommended replacement dose is reached.

Pregnancy

Pre-existing Hypothyroidism

LEVOLET dose requirements may increase during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at a minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. For patients with serum TSH above the normal trimester-specific range, increase the dose of LEVOLET by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable LEVOLET dose is reached and serum TSH is within the normal trimester-specific range. Reduce LEVOLET dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure LEVOLET dose is appropriate.

New Onset Hypothyroidism

Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs and symptoms of hypothyroidism, start LEVOLET at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH < 10 IU per liter) start LEVOLET at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust LEVOLET dosage until a serum TSH is within the normal trimester specific range [see Use In Specific Populations].

TSH Suppression In Well-differentiated Thyroid Cancer

Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a LEVOLET dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.

Monitoring TSH And/Or Thyroxine (T4) 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 LEVOLET 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 dose. In patients on a stable and appropriate replacement dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient’s clinical status.

Pediatrics

In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children 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 dose 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.

While 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 T4 to increase into the upper half of the normal range within 2 weeks of initiation of LEVOLET 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 LEVOLET [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Secondary And Tertiary Hypothyroidism

Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.

How Supplied

Dosage Forms And Strengths

LEVOLET tablets are available as follows:

 

Tablet Strength	Tablet Color/Shape	Tablet Markings
25 mcg	Orange/Round	“G/L” and “25”
50 mcg	White/Round	“G/L” and “50”
75 mcg	Violet/Round	“G/L” and “75”
88 mcg	Olive/Round	“G/L” and “88”
100 mcg	Yellow/Round	“G/L” and “100”
112 mcg	Rose/Round	“G/L” and “112”
125 mcg	Brown/Round	“G/L” and “125”
137 mcg	Turquoi se/Round	“G/L” and “137”
150 mcg	Blue/Round	“G/L and “150”
175 mcg	Lilac/Round	“G/L” and “175”
200 mcg	Pink/Round	“G/L” and “200”
300 mcg	Green/Round	“G/L” and “300”

 

Storage And Handling

LEVOLET (levothyroxine sodium, USP) tablets are supplied as follows:

 

Strength (mcg)	Color/Shape	Tablet Markings	NDC# for bottles of 90	NDC # for bottles of 100	NDC # for bottles of 1000
25	Orange/Round	“G/L” and “25”	64950-500-09	64950-500-01	64950-500-10
50	White/Round	“G/L” and “50”	64950-501-09	64950-501-01	64950-501-10
75	Violet/Round	“G/L” and “75”	64950-502-09	64950-502-01	64950-502-10
88	Olive/Round	“G/L” and “88”	64950-503-09	64950-503-01	64950-503-10
100	Yellow/Round	“G/L” and “100”	64950-504-09	64950-504-01	64950-504-10
112	Rose/Round	“G/L” and “112”	64950-505-09	64950-505-01	64950-505-10
125	Brown/Round	“G/L” and “125”	64950-506-09	64950-506-01	64950-506-10
137	Turquoise/Round	“G/L” and “137”	64950-507-09	64950-507-01	64950-507-10
150	Blue/Round	“G/L” and “150”	64950-508-09	64950-508-01	64950-508-10
175	Lilac/Round	“G/L” and “175”	64950-509-09	64950-509-01	64950-509-10
200	Pink/Round	“G/L” and “200”	64950-510-09	64950-510-01	64950-510-10
300	Green/Round	“G/L” and “300”	64950-511-09	64950-511-01	64950-511-10

 

Storage Conditions

Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. LEVOLET tablets should be protected from light and moisture.

Manufactured by: Genus Lifesciences Inc. Allentown, PA 18102. Revised: Dec 2021

Adverse reactions associated with LEVOLET therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see WARNINGS AND PRECAUTIONS, 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, 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 and 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.

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 LEVOLET (see Tables 2-5 below).

Table 2: Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of LEVOLET 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 LEVOLET at least 4 hours apart from these agents.
Orlistat	Monitor patients treated concomitantly with orlistat and LEVOLET for changes in thyroid function.
Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol) Ion Exchange Resins (e.g., Kayexalate)	Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer LEVOLET at least 4 hours prior to these drugs or monitor TSH levels.
Proton Pump Inhibitors Sucralfate Antacids (eg. aluminum & magnesium hydroxides, simethicone)	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.

 

Table 3: Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)

Drug or Drug Class	Effect
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid	These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with LEVOLET 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 Hydantoins Non-Steroidal Antiinflammatory Drugs – Fenamates	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.

 

Table 4: 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 LEVOLET requirements.
Drug or Drug Class	Effect
Phenobarbital Rifampin	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 a 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.

 

Table 5: Drugs That May Decrease Conversion of T4 to T3

Drug or Drug Class	Effect
Beta-adrenergic antagonists (eg. Propranolol > 160 mg/day)	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 (eg. Dexamethasone ≥4 mg/day)	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	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.

 

Antidiabetic Therapy

Addition of LEVOLET 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].

Oral Anticoagulants

LEVOLET 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 LEVOLET dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

Digitalis Glycosides

LEVOLET 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.

Antidepressant Therapy

Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and LEVOLET 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. LEVOLET may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on LEVOLET may result in increased LEVOLET requirements.

Ketamine

Concurrent use of ketamine and LEVOLET may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

Sympathomimetics

Concurrent use of sympathomimetics and LEVOLET 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.

Tyrosine-Kinase Inhibitors

Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients.

Drug-Food Interactions

Consumption of certain foods may affect LEVOLET absorption thereby necessitating adjustments in dosing [see DOSAGE AND ADMINISTRATION]. Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of LEVOLET from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

Drug-Laboratory Test Interactions

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.

Included as part of the PRECAUTIONS section.

Precautions

Cardiac Adverse Reactions In The Elderly and In Patients With Underlying Cardiovascular Disease

Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate LEVOLET therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].

Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive LEVOLET therapy. Monitor patients receiving concomitant LEVOLET and sympathomimetic agents for signs and symptoms of coronary insufficiency.

If cardiac symptoms develop or worsen, reduce the LEVOLET dose or withhold for one week and restart at a lower dose.

Myxedema Coma

Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma.

Acute Adrenal Crisis In Patients With Concomitant Adrenal Insufficiency

Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with LEVOLET [see CONTRAINDICATIONS].

Prevention Of Hyperthyroidism Or Incomplete Treatment Of Hypothyroidism

LEVOLET has a narrow therapeutic index. Over or undertreatment with LEVOLET may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and glucose and lipid metabolism. Titrate the dose of LEVOLET carefully and monitor response to titration to avoid these effects [see DOSAGE AND ADMINISTRATION]. Monitor for the presence of drug or food interactions when using LEVOLET and adjust the dose as necessary [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Worsening Of Diabetic Control

Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing LEVOLET [see DRUG INTERACTIONS].

Decreased Bone Mineral Density Associated With Thyroid Hormone Over-Replacement

Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Administer the minimum dose of LEVOLET that achieves the desired clinical and biochemical response to mitigate this risk.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Risk Summary

The clinical experience, including data from post-marketing studies, in pregnant women treated with oral levothyroxine to maintain a 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 LEVOLET dosage adjusted during pregnancy (see Clinical Considerations). Animal reproduction studies have not been conducted with levothyroxine sodium. LEVOLET 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 LEVOLET requirements. Serum TSH levels should be monitored and the LEVOLET dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the LEVOLET dosage should return to the pre-pregnancy dose immediately after delivery [see DOSAGE AND ADMINISTRATION].

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 LEVOLET and any potential adverse effects on the breastfed infant from LEVOLET or from the underlying maternal condition.

Pediatric Use

The initial dose of LEVOLET varies with age and body weight.

Dosing adjustments are based on an assessment of the individual patient’s clinical and laboratory parameters [see DOSAGE AND ADMINISTRATION].

In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue

LEVOLET administration for a trial period, but only after the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period and use laboratory test results and clinical assessment to guide diagnosis and treatment, if warranted.

Congenital Hypothyroidism [See DOSAGE AND ADMINISTRATION]

Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate LEVOLET therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients.

Closely monitor infants during the first 2 weeks of LEVOLET therapy for cardiac overload, arrhythmias, and aspiration from avid suckling.

Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.

Acquired Hypothyroidism In Pediatric Patients

Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height.

Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, initiate LEVOLET at less than the full replacement dose [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

The signs and symptoms of overdosage are those of hyperthyroidism [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. 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 LEVOLET dose 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.

Contraindications

LEVOLET is contraindicated in patients with uncorrected adrenal insufficiency [see WARNINGS AND PRECAUTIONS].

Mechanism Of Action

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.

The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

Pharmacodynamics

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.

Pharmacokinetics

Absorption

Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%. The majority of the LEVOLET dose is absorbed from the jejunum and upper ileum. The relative bioavailability of LEVOLET tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 absorption is increased by fasting and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption mayalsodecrease withage.Inaddition, many drugsandfoods affect T4 absorption [see DRUG INTERACTIONS].

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 T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. 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]. Thyroid hormones do not readily cross the placental barrier [see Use In Specific Populations].

Elimination

Metabolism

T4 is slowly eliminated (see Table 7). The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3). T3 and rT3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.

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 T4 is eliminated in the stool. Urinary excretion of T4 decreases with age.

Table 7: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone	Ratio in Thyroglobulin	Biologic Potency	t½ (days)	Protein Binding (%)a
Levothyroxine (T4)	10 -20	1	6-7 b	99.96
Liothyronine (T3)	1	4	≤ 2	99.5
a Includes TBG, TBPA, and TBA b 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism