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SYNTHROID - levothyroxine sodium tablet
SYNTHROID®(levothyroxine sodium tablets, USP)
DESCRIPTION
SYNTHROID (levothyroxine sodium tablets, USP) contain synthetic crystalline L-3,3',5,5'- tetraiodothyronine sodium salt [levothyroxine (T ) sodium]. Synthetic T 4 4 is identical to that produced in the human thyroid gland. Levothyroxine (T ) sodium has an empirical formula of 4 C 15 H 10 4I N NaO • H O, molecular weight of 798.86 g/mol (anhydrous), and structural formula 4 2 as shown:
Inactive Ingredients
Acacia, confectioner's sugar (contains corn starch), lactose monohydrate, magnesium stearate, povidone, and talc. The following are the color additives by tablet strength:
Strength (mcg) Color additive(s) 25 FD&C Yellow No. 6 Aluminum Lake 50 None 75 FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, 88 D&C Yellow No. 10 Aluminum Lake D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum 100 Lake 112 D&C Red No. 27 & 30 Aluminum Lake FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, 125 FD&C Blue No. 1 Aluminum Lake 137 FD&C Blue No. 1 Aluminum Lake 150 FD&C Blue No. 2 Aluminum Lake FD&C Blue No. 1 Aluminum Lake, D&C Red No. 27 & 30 Aluminum 175 Lake 200 FD&C Red No. 40 Aluminum Lake D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum 300 Lake, FD&C Blue No. 1 Aluminum Lake
4
Meets USP Dissolution Test 3
CLINICAL PHARMACOLOGY
Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin-stimulating hormone, TSH, from the anterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, L-thyroxine (T ) and L-triiodothyronine (T ), by the thyroid gland. Circulating serum T 3 3 and T 4 levels exert a feedback effect on both TRH and TSH secretion. When serum T 3 and T 4 levels increase, TRH and TSH secretion decrease. When thyroid hormone levels decrease, TRH and TSH secretion increase.
The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T 3 and 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.
Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development.
The physiological actions of thyroid hormones are produced predominantly by T , the majority 3 of which (approximately 80%) is derived from T 4 by deiodination in peripheral tissues.
Levothyroxine, at doses individualized according to patient response, is effective as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.
Levothyroxine is also effective in the suppression of pituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimoto's thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropin- dependent well-differentiated thyroid cancer (see INDICATIONS AND USAGE, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Pharmacokinetics
Absorption
Absorption of orally administered T 4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of SYNTHROID 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 soybean infant formula. Dietary fiber decreases bioavailability of T. Absorption may also decrease with age. 4 In addition, many drugs and foods affect T 4 absorption (see PRECAUTIONS - Drug Interactions and Drug-Food Interactions ).
Distribution
Pituitary TSH Suppression
In the treatment or prevention of various types of euthyroid goiters (see WARNINGS and PRECAUTIONS), including thyroid nodules (see WARNINGS and PRECAUTIONS ), subacute or chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter (see WARNINGS and PRECAUTIONS) and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.
CONTRAINDICATIONS
Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T 3 and T 4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids (see PRECAUTIONS). SYNTHROID is contraindicated in patients with hypersensitivity to any of the inactive ingredients in SYNTHROID tablets (See DESCRIPTION - Inactive Ingredients ).
WARNINGS
WARNING: Thyroid hormones, including SYNTHROID, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.
In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS). If the serum TSH level is not suppressed, SYNTHROID should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.
PRECAUTIONS
General
Levothyroxine has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or under-treatment. These consequences include, among others, effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Many drugs interact with levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response
(see Drug Interactions ).
Effects on Bone Mineral Density
In women, long-term levothyroxine sodium therapy has been associated with increased bone resorption, thereby decreasing bone mineral density, especially in post-menopausal women on greater than replacement doses or in women who are receiving suppressive doses of levothyroxine sodium. 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. Therefore, it is recommended that patients receiving levothyroxine sodium be given the minimum dose necessary to achieve the desired clinical and biochemical response.
Patients with Underlying Cardiovascular Disease
Exercise caution when administering levothyroxine to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease. In these patients, levothyroxine therapy should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease (see WARNINGS, PRECAUTIONS - Geriatric Use, and DOSAGE AND ADMINISTRATION). If cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and then cautiously restarted at a lower dose. Overtreatment with levothyroxine sodium may have adverse cardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias. Patients with coronary artery disease who are receiving levothyroxine therapy should be monitored closely during surgical procedures, since the possibility of precipitating cardiac arrhythmias may be greater in those treated with levothyroxine. Concomitant administration of levothyroxine and sympathomimetic agents to patients with coronary artery disease may precipitate coronary insufficiency.
Patients with Nontoxic Diffuse Goiter or Nodular Thyroid Disease
Exercise caution when administering levothyroxine to patients with nontoxic diffuse goiter or nodular thyroid disease in order to prevent precipitation of thyrotoxicosis (see WARNINGS ). If the serum TSH is already suppressed, levothyroxine sodium should not be administered (see CONTRAINDICATIONS ).
Associated Endocrine Disorders
Hypothalamic/pituitary hormone deficiencies
In patients with secondary or tertiary hypothyroidism, additional hypothalamic/pituitary hormone deficiencies should be considered, and, if diagnosed, treated (see PRECAUTIONS - Autoimmune polyglandular syndrome for adrenal insufficiency).
Autoimmune polyglandular syndrome
Occasionally, chronic autoimmune thyroiditis may occur in association with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus. Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of treatment with levothyroxine sodium. Failure to do so may precipitate an acute adrenal crisis when thyroid hormone therapy is initiated, due to increased
- SYNTHROID should not be used as a primary or adjunctive therapy in a weight control program.
- Keep SYNTHROID out of the reach of children. Store SYNTHROID away from heat, moisture, and light.
- Agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine sodium tablets. Therefore, levothyroxine sodium tablets should not be administered within 4 hours of these agents.
Laboratory Tests
General
The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation assay sensitivity ≤ 0.1 mIU/L or third generation assay sensitivity ≤ 0. mIU/L) and measurement of free-T. 4
The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. The choice of laboratory tests depends on various factors including the etiology of the underlying thyroid disease, the presence of concomitant medical conditions, including pregnancy, and the use of concomitant medications (see PRECAUTIONS - Drug Interactions and Drug-Laboratory Test Interactions). Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of SYNTHROID may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T 4 potency of the drug product.
Adults
In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after 8- weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6-12 months, depending on the clinical situation, and whenever there is a change in the patient's status. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving SYNTHROID (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Pediatrics
In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring both serum TSH (using a sensitive assay) and total- or free- T. 4 During the first three years of life, the serum total- or free- T 4 should be maintained at all times in the upper half of the normal range. While the aim of therapy is to also normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid
feedback threshold as a result ofin utero hypothyroidism. Failure of the serum T 4 to increase
into the upper half of the normal range within 2 weeks of initiation of SYNTHROID therapy and/or of the serum TSH to decrease below 20 mU/L within 4 weeks should alert the physician to the possibility that the child is not receiving adequate therapy. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of SYNTHROID.
The recommended frequency of monitoring of TSH and total or free T 4 in children is as follows: at 2 and 4 weeks after the initiation of treatment; every 1-2 months during the first year of life; every 2-3 months between 1 and 3 years of age; and every 3 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T 4 levels, and a physical examination, if indicated, be performed 2 weeks after any change in SYNTHROID dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals (see PRECAUTIONS - Pediatric Use and DOSAGE AND ADMINISTRATION).
Secondary (Pituitary) and Tertiary (Hypothalamic) Hypothyroidism
Adequacy of therapy should be assessed by measuring serum free- T 4 levels, which should be maintained in the upper half of the normal range in these patients.
Drug Interactions
Many drugs 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 SYNTHROID. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs. A listing of drug-thyroidal axis interactions is contained in Table 2.
The list of drug-thyroidal axis interactions in Table 2 may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware of this fact and should consult appropriate reference sources (e.g., package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected.
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur Use of these agents may result in a transient reduction in Dopamine/Dopamine Agonists TSH secretion when administered at the following doses: Glucocorticoids Dopamine (≥ 1 mcg/kg/min); Glucocorticoids Octreotide (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). Drugs that alter thyroid hormone secretion Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Long-term lithium therapy can result in goiter in up to 50%
TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral
contraceptives Androgens / Anabolic Steroids
Estrogens (oral) Asparaginase
Heroin / Methadone Glucocorticoids
5-Fluorouracil Slow-Release Nicotinic Acid
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Administration of these agents with levothyroxine results in Furosemide (> 80 mg IV) an initial transient increase in FT. Continued Heparin 4 administration results in a decrease in serum T 4 and Hydantoins normal FT 4 and TSH concentrations and, therefore, Non Steroidal Anti-Inflammatory patients are clinically euthyroid. Salicylates inhibit binding Drugs of T 4 and T 3 to TBG and transthyretin. An initial increase in
- Fenamates serum FT 4 is followed by return of FT 4 to normal levels with
- Phenylbutazone sustained therapeutic serum salicylate concentrations, Salicylates (> 2 g/day) although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation Carbamazepine of levothyroxine, resulting in increased levothyroxine Hydantoins requirements. Phenytoin and carbamazepine reduce serum Phenobarbital protein binding of levothyroxine, and total- and free- T 4 Rifampin may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T , leading to decreased T 3 3 Amiodarone (^) levels. However, serum T 4 levels are usually normal but Beta-adrenergic antagonists (^) may occasionally be slightly increased. In patients treated
- (e.g., Propranolol > 160 mg/day) (^) with large doses of propranolol (> 160 mg/day), T 3 and T 4 Glucocorticoids (^) levels change slightly, TSH levels remain normal, and
- (e.g., Dexamethasone ≥ 4 (^) patients are clinically euthyroid. It should be noted that
mg/day) (^) actions of particular beta-adrenergic antagonists may be
Propylthiouracil (PTU) (^) impaired when the hypothyroid patient is converted to the
euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors
(SSRIs; e.g., Sertraline)
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Cardiac Glycosides
Cytokines
- Interferon-α
- Interleukin-
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).
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. Concurrent use of tri/tetracyclic antidepressants and levothyroxine 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 CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to
Drug-Food Interactions
Consumption of certain foods may affect levothyroxine absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the GI tract.
Drug-Laboratory Test Interactions
Changes in TBG concentration must be considered when interpreting T 4 and T 3 values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free T 4 index (FT I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral 4 contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or corticosteroid therapy (see also Table 2). Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine. The synthetic T 4 in SYNTHROID is identical to that produced naturally by the human thyroid gland. Although there has been a reported association between prolonged thyroid hormone therapy and breast cancer, this has not been confirmed. Patients receiving SYNTHROID for appropriate clinical indications should be titrated to the lowest effective replacement dose.
Pregnancy
Category A
Studies in women taking levothyroxine sodium during pregnancy have not shown an increased risk of congenital abnormalities. Therefore, the possibility of fetal harm appears remote. SYNTHROID should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.
Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, pre-eclampsia, stillbirth and premature delivery. Maternal hypothyroidism may have an adverse effect on fetal and childhood growth and development. During pregnancy, serum T 4 levels may decrease and serum TSH levels increase to values outside the normal range. Since elevations in serum TSH may occur as early as 4 weeks gestation, pregnant women taking SYNTHROID should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of SYNTHROID. Since postpartum TSH levels are similar to preconception values, the SYNTHROID dosage should return to the pre-pregnancy dose immediately after delivery. A serum TSH level should be obtained 6-8 weeks postpartum.
Thyroid hormones cross the placental barrier to some extent as evidenced by levels in cord blood of athyreotic fetuses being approximately one-third maternal levels. Transfer of thyroid
hormone from the mother to the fetus, however, may not be adequate to preventin utero
hypothyroidism.
Nursing Mothers
Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when SYNTHROID is administered to a nursing woman. However, adequate replacement doses of levothyroxine are generally needed to maintain normal lactation.
Pediatric Use
General
The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development.
The initial dose of levothyroxine varies with age and body weight (see DOSAGE AND ADMINISTRATION - Table 3). Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters (see PRECAUTIONS - Laboratory Tests).
In children in whom a diagnosis of permanent hypothyroidism has not been established, it is recommended that levothyroxine administration be discontinued for a 30-day trial period, but only after the child is at least 3 years of age. Serum T 4 and TSH levels should then be obtained. If the T 4 is low and the TSH high, the diagnosis of permanent hypothyroidism is established, and levothyroxine therapy should be reinstituted. If the T 4 and TSH levels are normal, euthyroidism may be assumed and, therefore, the hypothyroidism can be considered to have been transient. In this instance, however, the physician should carefully monitor the child and repeat the thyroid function tests if any signs or symptoms of hypothyroidism develop. In this setting, the clinician should have a high index of suspicion of relapse. If the results of the levothyroxine withdrawal test are inconclusive, careful follow-up and subsequent testing will be necessary.
Since some more severely affected children may become clinically hypothyroid when treatment is discontinued for 30 days, an alternate approach is to reduce the replacement dose of levothyroxine by half during the 30-day trial period. If, after 30 days, the serum TSH is elevated above 20 mU/L, the diagnosis of permanent hypothyroidism is confirmed, and full replacement therapy should be resumed. However, if the serum TSH has not risen to greater than 20 mU/L, levothyroxine treatment should be discontinued for another 30-day trial period followed by repeat serum T 4 and TSH testing.
The presence of concomitant medical conditions should be considered in certain clinical circumstances and, if present, appropriately treated (see PRECAUTIONS ).
Congenital Hypothyroidism
(see PRECAUTIONS - Laboratory Tests and DOSAGE AND ADMINISTRATION)
Rapid restoration of normal serum T 4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, SYNTHROID therapy should be initiated immediately upon diagnosis and is generally continued for life.
During the first 2 weeks of SYNTHROID therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration from avid suckling.
diarrhea, vomiting, abdominal cramps and elevations in liver function tests;
Dermatologic
hair loss, flushing;
Endocrine
decreased bone mineral density;
Reproductive
menstrual irregularities, impaired fertility.
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.
Seizures have been reported rarely with the institution of levothyroxine therapy.
Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism.
Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.
OVERDOSAGE
The signs and symptoms of overdosage are those of hyperthyroidism (see PRECAUTIONS and ADVERSE REACTIONS). In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures have occurred in a child ingesting 18 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.
Treatment of Overdosage
Levothyroxine sodium should be reduced in dose or temporarily discontinued if signs or symptoms of overdosage occur.
Acute Massive Overdosage
This may be a life-threatening emergency, therefore, symptomatic and supportive therapy should be instituted immediately. If not contraindicated (e.g., by seizures, coma, or loss of the gag reflex), the stomach should be emptied by emesis or gastric lavage to decrease gastrointestinal absorption. Activated charcoal or cholestyramine may also be used to decrease absorption. Central and peripheral increased sympathetic activity may be treated by administering β-receptor antagonists, e.g., propranolol, provided there are no medical contraindications to their use. Provide respiratory support as needed; control congestive heart failure and arrhythmia; control fever, hypoglycemia, and fluid loss as necessary. Large doses of antithyroid drugs (e.g., methimazole or propylthiouracil) followed in one to two hours by
large doses of iodine may be given to inhibit synthesis and release of thyroid hormones. Glucocorticoids may be given to inhibit the conversion of T 4 to T. Plasmapheresis, charcoal 3 hemoperfusion and exchange transfusion have been reserved for cases in which continued clinical deterioration occurs despite conventional therapy. Because T 4 is highly protein bound, very little drug will be removed by dialysis.
DOSAGE AND ADMINISTRATION
General Principles
The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of SYNTHROID that is adequate to achieve these goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated (see WARNINGS and PRECAUTIONS). Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters (see PRECAUTIONS - Laboratory Tests).
SYNTHROID is administered as a single daily dose, preferably one-half to one-hour before breakfast. SYNTHROID should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see PRECAUTIONS - Drug Interactions).
Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4-6 weeks.
Caution should be exercised when administering SYNTHROID to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS ).
Specific Patient Populations
Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete
(see WARNINGS and PRECAUTIONS - Laboratory Tests)
Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 years who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g., 100- mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium doses greater than 200 mcg/day are seldom required. An inadequate response to daily doses ≥ 300 mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug
interactions.
For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at 6-8 week intervals, as needed. The recommended starting dose of levothyroxine sodium in elderly patients with cardiac disease is 12.5-25 mcg/day , with gradual dose increments at 4-6 week intervals. The levothyroxine sodium dose is generally adjusted in 12.5-25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized.
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
12 years but growth and puberty incomplete 2-3 mcg/kg/day Growth and puberty complete 1.7 mcg/kg/day a The dose should be adjusted based on clinical response and laboratory parameters (see PRECAUTIONS - Laboratory Tests and Pediatric Use).
Pregnancy
Pregnancy may increase levothyroxine requirements (see PREGNANCY).
Subclinical Hypothyroidism
If this condition is treated, a lower levothyroxine sodium dose (e.g., 1 mcg/kg/day) than that used for full replacement may be adequate to normalize the serum TSH level. Patients who are not treated should be monitored yearly for changes in clinical status and thyroid laboratory parameters.
TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules
The target level for TSH suppression in these conditions has not been established with controlled studies. In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of SYNTHROID used for TSH suppression should be individualized based on the specific disease and the patient being treated.
In the treatment of well-differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy. Generally, TSH is suppressed to < 0. mU/L, and this usually requires a levothyroxine sodium dose of greater than 2 mcg/kg/day. However, in patients with high-risk tumors, the target level for TSH suppression may be < 0. mU/L.
In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target (e.g., 0.1 to either 0.5 or 1.0 mU/L) than that used for the treatment of thyroid cancer. Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS - WARNINGS and PRECAUTIONS).
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. Therefore, oral thyroid hormone drug products are not recommended to treat this condition. Thyroid hormone products formulated for intravenous administration should be administered.
HOW SUPPLIED
SYNTHROID (levothyroxine sodium tablets, USP) are round, color coded, scored and debossed with "SYNTHROID" on one side and potency on the other side. They are supplied as follows:
Strength NDC # for bottles of NDC # for bottles of NDC # for unit dose (mcg) Color 100 1000 cartons of 100 25 orange 0074-4341-13 0074-4341-19 - - 50 white 0074-4552-13 0074-4552-19 0074-4552- 75 violet 0074-5182-13 0074-5182-19 0074-5182- 88 olive 0074-6594-13 0074-6594-19 - - 100 yellow 0074-6624-13 0074-6624-19 0074-6624- 112 rose 0074-9296-13 0074-9296-19 - - 125 brown 0074-7068-13 0074-7068-19 0074-7068- 137 turquoise 0074-3727-13 0074-3727-19 - - 150 blue 0074-7069-13 0074-7069-19 0074-7069- 175 lilac 0074-7070-13 0074-7070-19 - - 200 pink 0074-7148-13 0074-7148-19 0074-7148- 300 green 0074-7149-13 0074-7149-19 - -
Storage Conditions
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. SYNTHROID tablets should be protected from light and moisture.
Abbott Laboratories
North Chicago, IL 60064, U.S.A.
