sparaginase glucocorticoids slow-release nicotinic acid these drugs may decrease serum tbg concentration. potential impact (below): administration of these agents with levothyroxine results in an initial transient increase in ft 4 . continued administration results in a decrease in serum t 4 and normal ft 4 and tsh concentrations. salicylates (> 2 g/day) salicylates inhibit binding of t 4 and t 3 to tbg and transthyretin. an initial increase in serum ft 4 is followed by return of ft 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total t 4 levels may decrease by as much as 30%. other drugs: 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 2: drugs that may alter hepatic metabolism of t 4 (hypothyroidism) potential impact: stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine 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 changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism.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 3: drugs that may decrease conversion of t 4 to t 3 potential impact: administration of these enzyme inhibitors decreases the peripheral conversion of t 4 to t 3 , leading to decreased t 3 levels. however, serum t 4 levels are usually normal but may occasionally be slightly increased. drug or drug class effect beta-adrenergic antagonists (e.g., propranolol > 160 mg/day) in patients treated with large doses of propranolol (> 160 mg/day), t 3 and t 4 levels change slightly, tsh levels remain normal, and patients are clinically euthyroid. it should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. glucocorticoids (e.g., dexamethasone ≥ 4 mg/day) short-term administration of large doses of glucocorticoids may decrease serum t 3 concentrations by 30% with minimal change in serum t 4 levels. however, long-term glucocorticoid therapy may result in slightly decreased t 3 and t 4 levels due to decreased tbg production (see above). other drugs: amiodarone 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 levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. careful monitoring of glycemic control is recommended. 7.3 oral anticoagulants levothyroxine increases the response to oral anticoagulant therapy. therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state. closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 digitalis glycosides levothyroxine may reduce the therapeutic effects of digitalis glycosides. serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. 7.5 antidepressant therapy concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. levothyroxine may accelerate the onset of action of tricyclics. administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. 7.6 ketamine concurrent use of ketamine and levothyroxine may produce marked hypertension and tachycardia. closely monitor blood pressure and heart rate in these patients. 7.7 sympathomimetics concurrent use may of sympathomimetics and levothyroxine 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 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 concentrations. nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease tbg concentration. familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of tbg deficiency approximating 1 in 9,000.

5.3 ). 5.1 cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease overtreatment with levothyroxine sodium injection may cause arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death, particularly in patients with cardiovascular disease and in elderly patients. start with lower doses in elderly patients and in patients with underlying cardiovascular disease and monitor patients after administration of levothyroxine sodium injection for cardiac adverse reactions. 5.2 acute adrenal crisis in patients with concomitant adrenal insufficiency chronic autoimmune thyroiditis, which can lead to myxedema coma, may occur in association with other autoimmune disorders such as 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 [see contraindications ( 4 )]. treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with levothyroxine sodium injection. 5.3 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 [see drug interactions ( 7.2 )].

doses in elderly patients and in patients with underlying cardiovascular disease [see warnings and precautions ( 5.1 ) and use in specific populations ( 8.5 )]. the recommended loading dose of levothyroxine sodium injection is 300 mcg to 500 mcg administered intravenously. the recommended maintenance dose of levothyroxine sodium injection is 50 mcg to 100 mcg administered intravenously daily until the patient can tolerate oral therapy. 2.2 administration instructions administer levothyroxine sodium injection as an intravenous injection at a rate not to exceed 100 mcg per minute. do not add levothyroxine sodium injection to intravenous fluids. inspect levothyroxine sodium injection visually prior to injection. it should appear clear and colorless, solution free of visible particulates. do not use if particulate matter or coloration is seen. discard any unused portion.

fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating, headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia, tremors, muscle weakness, muscle spasm, palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest, dyspnea, diarrhea, vomiting, abdominal cramps, elevations in liver function tests, flushing, and rash. ( 6 ) to report suspected adverse reactions, contact fresenius kabi usa, llc at 1-800-551-7176 or fda at 1-800-fda-1088 or www.fda.gov/medwatch. 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.

sparaginase glucocorticoids slow-release nicotinic acid these drugs may decrease serum tbg concentration. potential impact (below): administration of these agents with levothyroxine results in an initial transient increase in ft 4 . continued administration results in a decrease in serum t 4 and normal ft 4 and tsh concentrations. salicylates (> 2 g/day) salicylates inhibit binding of t 4 and t 3 to tbg and transthyretin. an initial increase in serum ft 4 is followed by return of ft 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total t 4 levels may decrease by as much as 30%. other drugs: 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 2: drugs that may alter hepatic metabolism of t 4 (hypothyroidism) potential impact: stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine 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 3: drugs that may decrease conversion of t 4 to t 3 potential impact: administration of these enzyme inhibitors decreases the peripheral conversion of t 4 to t 3 , leading to decreased t 3 levels. however, serum t 4 levels are usually normal but may occasionally be slightly increased. drug or drug class effect beta-adrenergic antagonists (e.g., propranolol > 160 mg/day) in patients treated with large doses of propranolol (> 160 mg/day), t 3 and t 4 levels change slightly, tsh levels remain normal, and patients are clinically euthyroid. it should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. glucocorticoids (e.g., dexamethasone ≥ 4 mg/day) short-term administration of large doses of glucocorticoids may decrease serum t 3 concentrations by 30% with minimal change in serum t 4 levels. however, long-term glucocorticoid therapy may result in slightly decreased t 3 and t 4 levels due to decreased tbg production (see above). other drugs: amiodarone 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 levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. careful monitoring of glycemic control is recommended. 7.3 oral anticoagulants levothyroxine increases the response to oral anticoagulant therapy. therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state. closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 digitalis glycosides levothyroxine may reduce the therapeutic effects of digitalis glycosides. serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. 7.5 antidepressant therapy concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. levothyroxine may accelerate the onset of action of tricyclics. administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. 7.6 ketamine concurrent use of ketamine and levothyroxine may produce marked hypertension and tachycardia. closely monitor blood pressure and heart rate in these patients. 7.7 sympathomimetics concurrent use may of sympathomimetics and levothyroxine 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 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 concentrations. nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease tbg concentration. familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of tbg deficiency approximating 1 in 9,000.

d. delaying treatment in pregnant women with myxedema coma increases the risk of maternal and fetal morbidity and mortality. life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of levothyroxine sodium injection on the fetus. data human data there is no available data with use of levothyroxine sodium injection in pregnant women. oral levothyroxine is approved for use as a replacement therapy in hypothyroidism. there is a long experience of oral levothyroxine use in pregnant women that has 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 published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. 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. there is no available data with use of levothyroxine sodium injection in lactating women. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for levothyroxine and any potential adverse effects on the breastfed infant from levothyroxine or from the underlying maternal condition. 8.4 pediatric use the safety and efficacy of levothyroxine sodium injection have not been established in pediatric patients. 8.5 geriatric use because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium injection with lower doses in elderly patients and in patients with underlying cardiovascular disease and closely monitor for cardiac adverse reactions. atrial arrhythmias can occur in elderly patients. atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly [see dosage and administration ( 2.1 ) and warnings and precautions ( 5.1 )].

ant women with myxedema coma increases the risk of maternal and fetal morbidity and mortality. life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of levothyroxine sodium injection on the fetus. data human data there is no available data with use of levothyroxine sodium injection in pregnant women. oral levothyroxine is approved for use as a replacement therapy in hypothyroidism. there is a long experience of oral levothyroxine use in pregnant women that has not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women.

ose 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 )]. metabolism t4 is slowly eliminated. the major pathway of thyroid hormone metabolism is through sequential deiodination. approximately eighty percent 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, where it is hydrolyzed and eliminated in feces as the free hormones. urinary excretion of t4 decreases with age. table 1: pharmacokinetic parameters of thyroid hormones in euthyroid patients t 4 : levothyroxine t 3 : liothyronine 1 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism. 2 includes tbg, tbpa, and tba. hormone ratio in thyroglobulin biologic potency half-life (days) protein binding (%) 2 t 4 10 to 20 1 6 to 8 1 99.96 t 3 1 4 ≤ 2 99.5

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, where it is hydrolyzed and eliminated in feces as the free hormones. urinary excretion of t4 decreases with age. table 1: pharmacokinetic parameters of thyroid hormones in euthyroid patients t 4 : levothyroxine t 3 : liothyronine 1 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism. 2 includes tbg, tbpa, and tba. hormone ratio in thyroglobulin biologic potency half-life (days) protein binding (%) 2 t 4 10 to 20 1 6 to 8 1 99.96 t 3 1 4 ≤ 2 99.5