minister levo-t at least 4 hours apart from these agents. orlistat monitor patients treated concomitantly with orlistat and levo-t for changes in thyroid function. bile acid sequestrants -colesevelam -cholestyramine -colestipol ion exchange resins -kayexalate -sevelamer bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. administer levo-t at least 4 hours prior to these drugs or monitor tsh levels. other drugs: proton pump inhibitors sucralfate antacids - 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 levo-t 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 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 t3 potential impact: administration of these enzyme inhibitors decreases the peripheral conversion of t4 to t3, leading to decreased t3 levels. however, serum t4 levels are usually normal but may occasionally be slightly increased. drug or drug class effect beta-adrenergic antagonists (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 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.

thyrotropin-dependent well-differentiated thyroid cancer. limitations of use: levo-t 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 levo-t may induce hyperthyroidism [see warnings and precautions (5.4) ]. levo-t is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

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 ) 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.

least 4 hours before or after drugs known to interfere with levo-t absorption [see drug interactions (7.1) ] . evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect levo-t absorption [see drug interactions (7.9) and clinical pharmacology (12.3) ] . 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 weight 0-3 months 10-15 mcg/kg/day 3-6 months 8-10 mcg/kg/day 6-12 months 6-8 mcg/kg/day 1-5 years 5-6 mcg/kg/day 6-12 years 4-5 mcg/kg/day greater than 12 years but growth and 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 for tsh suppression may be lower. 2.4 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 levo-t 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 levo-t therapy and/or of the serum tsh to decrease below 20 iu per liter within 4 weeks may indicate the child is not receiving adequate therapy. assess compliance, dose of medication administered, and method of administration prior to increasing the dose of levo-t [see warnings and precautions (5.1) and use in specific populations (8.4) ] . secondary and tertiary hypothyroidism monitor serum free-t4 levels and maintain in the upper half of the normal range in these patients.

ted 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 . 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.

minister levo-t at least 4 hours apart from these agents. orlistat monitor patients treated concomitantly with orlistat and levo-t for changes in thyroid function. bile acid sequestrants -colesevelam -cholestyramine -colestipol ion exchange resins -kayexalate -sevelamer bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. administer levo-t at least 4 hours prior to these drugs or monitor tsh levels. other drugs: proton pump inhibitors sucralfate antacids - 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 levo-t 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 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 t3 potential impact: administration of these enzyme inhibitors decreases the peripheral conversion of t4 to t3, leading to decreased t3 levels. however, serum t4 levels are usually normal but may occasionally be slightly increased. drug or drug class effect beta-adrenergic antagonists (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 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.

es 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 levo-t requirements. serum tsh levels should be monitored and the levo-t dosage adjusted during pregnancy. since postpartum tsh levels are similar to preconception values, the levo-t dosage should return to the pre-pregnancy dose immediately after delivery [see dosage and administration (2.3) ]. data human data levothyroxine is approved for use as a replacement therapy for hypothyroidism. there is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women. 8.2 lactation 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.

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 levo-t requirements. serum tsh levels should be monitored and the levo-t dosage adjusted during pregnancy. since postpartum tsh levels are similar to preconception values, the levo-t dosage should return to the pre-pregnancy dose immediately after delivery [see dosage and administration (2.3) ]. data human data levothyroxine is approved for use as a replacement therapy for hypothyroidism. there is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women.

ts. 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.

lative bioavailability of levo-t tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 99%. 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 may also decrease with age. in addition, many drugs and foods affect t4 absorption [see drug interactions (7) ] . distribution circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (tbg), thyroxine-binding prealbumin (tbpa), and albumin (tba), whose capacities and affinities vary for each hormone. the higher affinity of both tbg and tbpa for 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 (7) ] . thyroid hormones do not readily cross the placental barrier [see use in specific populations (8.1) ] . 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 t 1/2 (days) protein binding (%) 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

, 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 (7) ] . thyroid hormones do not readily cross the placental barrier [see use in specific populations (8.1) ] . 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 t 1/2 (days) protein binding (%) 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

usp controlled room temperature]. levo-t tablets should be protected from light and moisture.

d 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, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking levo-t. if they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. if patients are taking anticoagulants, their clotting status should be checked frequently. instruct patients to notify their physician or dentist that they are taking levo-t prior to any surgery. adverse reactions instruct patients to notify their healthcare provider if they experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event. inform patients that partial hair loss may occur rarely during the first few months of levo-t therapy, but this is usually temporary.