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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LEVO-T® safely and effectively. See full prescribing information for LEVO-T.
LEVO-T® (levothyroxine sodium) tablets, for oral use Initial U.S. Approval: 2002
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS See full prescribing information for complete boxed warning
- Thyroid hormones, including Levo-T 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).
----------------------------INDICATIONS AND USAGE-------------------------- LEVO-T is L-thyroxine (T4) indicated 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. -----------------------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 4-6 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 T4 as well as clinical status. (2.4) -----------------------DOSAGE FORMS AND STRENGTHS------------------- Tablets: 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 mcg (3)
--------------------------------CONTRAINDICATIONS----------------------------
- Uncorrected adrenal insufficiency. (4) ------------------------WARNINGS AND PRECAUTIONS-----------------
- Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate LEVO-T at less than the full replacement dose because of the increased risk of cardiac adverse reactions, including atrial fibrillation. (2.3, 5.1, 8.5)
- Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. (5.2)
- Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement glucocorticoids prior to initiation of LEVO-T treatment. (5.3)
- Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper dose titration and careful monitoring is critical to prevent the persistence of hypothyroidism or the development of hyperthyroidism. (5.4)
- Worsening of diabetic control: 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 thyroid hormone therapy. (5.5)
- Decreased bone mineral density associated with thyroid hormone over- replacement: Over-replacement can increase bone resorption and decrease bone mineral density. Give the lowest effective dose. (5.6) --------------------------------ADVERSE REACTIONS---------------------------- Adverse reactions associated with LEVO-T 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 Neolpharma, Inc. at 1-844-200-4163 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------------------------------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 LEVO-T. (7) -------------------------USE IN SPECIFIC POPULATIONS--------------------- Pregnancy may require the use of higher doses of LEVO-T. (2.3, 8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/
FULL PRESCRIBING INFORMATION: CONTENTS WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION* 2.1 General Administration Information 2.2 General Principles of Dosing 2.3 Dosing in Specific Patient Populations 2.4 Monitoring TSH and/or Thyroxine (T4) Levels 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease 5.2 Myxedema Coma 5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 5.5 Worsening of Diabetic Control 5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 7.2 Antidiabetic Therapy 7.3 Oral Anticoagulants 7.4 Digitalis Glycosides
7.5 Antidepressant Therapy 7.6 Ketamine 7.7 Sympathomimetics 7.8 Tyrosine-Kinase Inhibitors 7.9 Drug-Food Interactions 7.10 Drug-Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
Administer LEVO-T 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. Do not store the suspension. Do not administer in foods that decrease absorption of LEVO-T, such as soybean- based infant formula [see Drug Interactions (7.9)].
2.2 General Principles of Dosing
The dose of LEVO-T 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 dose adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.4)].
The peak therapeutic effect of a given dose of LEVO-T may not be attained for 4 to 6 weeks.
2.3 Dosing in Specific Patient Populations
Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete
Start LEVO-T 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 LEVO-T 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 LEVO-T 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 LEVO-T 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 LEVO-T 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 LEVO-T 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 LEVO-T in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start LEVO-T 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 (2.4)].
Table 1. LEVO-T 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 (2.4) and Use in Specific Populations (8.4)].
Newborns (0-3 months) at risk for cardiac failure : Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response.
Children at risk for hyperactivity : To minimize the risk of hyperactivity in children, 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: LEVO-T dose requirements may increase during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at 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 LEVO-T by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable LEVO-T dose is reached and serum TSH is within the normal trimester- specific range. Reduce LEVO-T dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure LEVO-T 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 LEVO-T 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 LEVO-T at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust LEVO-T dosage until a serum TSH is within the normal trimester specific range [see Use in Specific Populations (8.1)].
TSH Suppression in Well-differentiated Thyroid Cancer
Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a LEVO-T dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level
175 mcg Lilac/ Caplet “175” and “GG/339” 200 mcg Pink/ Caplet “200” and “GG/340” 300 mcg Green/ Caplet “300” and “GG/341”
4 CONTRAINDICATIONS
LEVO-T is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (5.3)].
5 WARNINGS AND PRECAUTIONS
5.1 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 LEVO-T therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Dosage and Administration (2.3), Use in Specific Populations (8.5)].
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive LEVO-T therapy. Monitor patients receiving concomitant LEVO T and sympathomimetic agents for signs and symptoms of coronary insufficiency.
If cardiac symptoms develop or worsen, reduce the LEVO-T dose or withhold for one week and restart at a lower dose.
5.2 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.
5.3 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 LEVO-T [see Contraindications (4)].
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism
LEVO-T has a narrow therapeutic index. Over- or undertreatment with LEVO-T 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 LEVO-T carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4)]. Monitor for the presence of drug or food interactions when using LEVO-T and adjust the dose as necessary [see Drug Interactions (7.9) and Clinical Pharmacology (12.3)].
5.5 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 LEVO-T [see Drug Interactions (7.2)].
5.6 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 LEVO-T that achieves the desired clinical and biochemical response to mitigate this risk.
6 ADVERSE REACTIONS
Adverse reactions associated with LEVO-T 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 Children
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.
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.
7 DRUG INTERACTIONS
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics
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 Anti-inflammatory 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 LEVO-T 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 T
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class Effect
Beta-adrenergic antagonists (e.g., 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 (e.g., 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.
7.2 Antidiabetic Therapy
Addition of LEVO-T 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
LEVO-T 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 LEVO-T dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.
7.4 Digitalis Glycosides
LEVO-T 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 LEVO-T 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. LEVO-T may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on LEVO-T may result in increased LEVO-T requirements.
7.6 Ketamine
Concurrent use of ketamine and LEVO-T may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.
7.7 Sympathomimetics
Concurrent use of sympathomimetics and LEVO-T 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 LEVO-T 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 LEVO-T from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.
7.10 Drug-Laboratory Test Interactions
Risk Summary
Limited published studies report that levothyroxine is present in human milk. However, there is insufficient information to determine the effects of Levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEVO-T and any potential adverse effects on the breastfed infant from LEVO-T or from the underlying maternal condition.
8.4 Pediatric Use
The initial dose of LEVO-T 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 (2.3, 2.4)].
In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue LEVO-T 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 (2.3, 2.4)]
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 LEVO-T therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients.
Closely monitor infants during the first 2 weeks of LEVO-T 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.
8.5 Geriatric Use
Because of the increased prevalence of cardiovascular disease among the elderly, initiate LEVO T at less than the full replacement dose [see Warnings and Precautions (5.1) and Dosage and Administration (2.3)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the
most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.
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 LEVO-T 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.
11 DESCRIPTION
LEVO-T (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 C 15 H 10 I 4 NNaO 4 •x H 2 O (where x = 5), molecular weight of 798.86 g/mol (anhydrous), and structural formula as shown:
LEVO-T 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 LEVO-T tablet contains the inactive ingredients Magnesium Stearate, NF; Microcrystalline Cellulose, NF; Colloidal Silicone Dioxide, NF; and Sodium Starch Glycolate, NF. Each tablet strength meets USP Dissolution Test 2. Table 6 provides a listing of the color additives by tablet strength:
Table 6. LEVO-T Tablets Color Additives
Strength (mcg)
Color additive(s)
25 FD&C Yellow No. 6 Aluminum Lake 50 None 75 FD&C Blue No. 2 Aluminum Lake, D&C Red No. 27 Aluminum Lake 88 FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, D&C Red No. 30 Aluminum Lake 100 D&C Yellow No. 10 Aluminum Lake, D&C Red Lake Blend (D&C Red No. 27 Lake and D&C Red No. 30 Lake)
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 T 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 T 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 t1/2 (days) (^) Protein Binding (%)a Levothyroxine (T4) 10 - (^20 1 6) - 7 b^ 99.
Liothyronine (T3) 1 4 ≤ 2 99.
a. Includes TBG, TBPA, and TBA b. 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine.
16 HOW SUPPLIED/STORAGE AND HANDLING
LEVO-T (levothyroxine sodium, USP) tablets are supplied as follows:
Strength (mcg)
Color/Shape Tablet Markings NDC# for bottles of 90
NDC # for bottles of 1000 (^25) Orange/Caplet “25” and “GG/331” 55466-104-11 55466-104-
(^50) White/ Caplet “50” and “GG/332” 55466-105-11 55466-105-
(^75) Violet/ Caplet “75” and “GG/333” 55466-106-11 55466-106-
(^88) Olive Green/ Caplet “88” and ‘GG/334” 55466-107-11 -
(^100) Yellow/ Caplet “100” and “GG/335” 55466-108-11 55466-108-
(^112) Rose/ Caplet “112” and “GG/336” 55466-109-11 -
(^125) Brown/ Caplet “125” and “GG/337” 55466-110-11 55466-110-
(^137) Turquoise/ Caplet “137” and “GG/330” 55466-111-11 -
(^150) Blue/ Caplet “150” and “GG/338” 55466-112-11 -
(^175) Lilac/ Caplet “175” and “GG/339” 55466-113-11 -
(^200) Pink/ Caplet “200” and “GG/340” 55466-114-11 -
(^300) Green/ Caplet “300” and “GG/341” 55466-115-11 -
Storage Conditions
Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. LEVO-T tablets should be protected from light and moisture.
17 PATIENT COUNSELING INFORMATION
Inform the patient of the following information to aid in the safe and effective use of LEVO-T :
Dosing and Administration
- Instruct patients that LEVO-T should be taken with a full glass of water since the tablet may rapidly disintegrate.
- Instruct patients to take LEVO-T only as directed by their healthcare provider.
- Instruct patients to take LEVO-T 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 LEVO-T 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 LEVO-T.
Important Information
- Inform patients that it may take several weeks before they notice an improvement in symptoms.
- Inform patients that the levothyroxine in LEVO-T 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 LEVO-T 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,
