iate and timely dosage adjustments. 7.3 digitalis glycosides the therapeutic effects of digitalis glycosides may be reduced by levothyroxine. serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. 7.4 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 cns stimulation; onset of action of tricyclics may be accelerated. administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. 7.5 ketamine concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. 7.6 sympathomimetics concurrent use 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. 7.7 drug-laboratory test interactions changes in thyroxine binding globulin (tbg) concentration must be considered when interpreting levothyroxine and triiodothyronine values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free levothyroxine index. pregnancy, infectious hepatitis, estrogens, estrogen containing oral 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. familial hyper or hypo thyroxine binding globulinemias have been described, with the incidence of tbg deficiency approximating 1 in 9,000. 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 levothyroxine sodium for injection. ( 7 , 12.3 )

ociation with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and insulin–dependent diabetes mellitus. patients should be treated with replacement glucocorticoids prior to initiation of treatment with levothyroxine sodium for injection, until adrenal function has been adequately assessed. failure to do so may precipitate an acute adrenal crisis when thyroid hormone therapy is initiated, due to increased metabolic clearance of glucocorticoids by thyroid hormone. with initiation of levothyroxine sodium for injection, patients with myxedema coma should also be monitored for previously undiagnosed diabetes insipidus. 5.3 not indicated for treatment of obesity thyroid hormones, including levothyroxine sodium for injection, 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 [ see adverse reactions ( 6 ) and overdosage ( 10 ) ]. • excessive bolus doses of levothyroxine sodium for injection (> 500 mcg) are associated with cardiac complications, particularly in the elderly and in patients with an underlying cardiac condition. initiate therapy with doses at the lower end of the recommended range. ( 5.1 ) • close observation of the patient following the administration of levothyroxine sodium for injection is advised. ( 5.1 ) • levothyroxine sodium for injection therapy for patients with previously undiagnosed endocrine disorders, including adrenal insufficiency, hypopituitarism, and diabetes insipidus, may worsen symptoms of these endocrinopathies. ( 5.2 )

euthyroid state. relative bioavailability between levothyroxine sodium for injection and oral levothyroxine products has not been established. based on medical practice, the relative bioavailability between oral and intravenous administration of levothyroxine sodium for injection is estimated to be from 48 to 74%. due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, tsh and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly. 2.2 dosing in the elderly and in patients with cardiovascular disease intravenous levothyroxine may be associated with cardiac toxicity-including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death-in the elderly and in those with underlying cardiovascular disease. therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations. 2.3 reconstitution directions reconstitute the lyophilized levothyroxine sodium for injection by aseptically adding 5 ml of 0.9% sodium chloride injection, usp only. shake vial to ensure complete mixing. the resultant solution will have a final concentration of approximately 20 mcg per ml and 100 mcg per ml for the 100 mcg and 500 mcg vials, respectively. reconstituted drug product is preservative free and is stable for 4 hours. discard any unused portion. do not add levothyroxine sodium for injection to other iv fluids. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. • an initial intravenous loading dose of levothyroxine sodium for injection between 300 to 500 mcg followed by once daily intravenous maintenance doses between 50 and 100 mcg should be administered, as clinically indicated, until the patient can tolerate oral therapy. ( 2.1 ) • reconstitute the lyophilized levothyroxine sodium for injection by aseptically adding 5 ml of 0.9% sodium chloride injection, usp. shake vial to ensure complete mixing. reconstituted drug product is preservative free. use immediately after reconstitution. discard any unused portion. ( 2.3 ) • do not add to other iv fluids. ( 2.3 )

iate and timely dosage adjustments. 7.3 digitalis glycosides the therapeutic effects of digitalis glycosides may be reduced by levothyroxine. serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. 7.4 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 cns stimulation; onset of action of tricyclics may be accelerated. administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. 7.5 ketamine concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. 7.6 sympathomimetics concurrent use 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. 7.7 drug-laboratory test interactions changes in thyroxine binding globulin (tbg) concentration must be considered when interpreting levothyroxine and triiodothyronine values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free levothyroxine index. pregnancy, infectious hepatitis, estrogens, estrogen containing oral 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. familial hyper or hypo thyroxine binding globulinemias have been described, with the incidence of tbg deficiency approximating 1 in 9,000. 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 levothyroxine sodium for injection. ( 7 , 12.3 )

required to maintain normal lactation. there are no reported cases of levothyroxine sodium for injection used to treat myxedema coma in patients who are lactating. however, such patients should be treated with levothyroxine sodium for injection as the risk of nontreatment is associated with a high probability of significant morbidity or mortality to the nursing patient. 8.4 pediatric use myxedema coma is a disease of the elderly. an approved, oral dosage form of levothyroxine should be used in the pediatric patient population for maintaining a euthyroid state in non-complicated hypothyroidism. 8.5 geriatric use and patients with underlying cardiovascular disease see section 2, dosage and administration, for full prescribing information in the geriatric patient population. because of the increased prevalence of cardiovascular disease in the elderly, cautious use of levothyroxine sodium for injection in the elderly and in patients with known cardiac risk factors is advised. atrial fibrillation is a common side effect associated with levothyroxine treatment in the elderly [ see dosage and administration ( 2 ) and warnings and precautions ( 5 ) ]. • elderly and those with underlying cardiovascular disease should receive doses at the lower end of the recommended range. ( 8.5 ) revised 05/2022

gland. circulating serum t 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 increases. tsh is used for the diagnosis of hypothyroidism and evaluation of levothyroxine therapy adequacy with other laboratory and clinical data. [see dosage ( 2.1 )] there are drugs known to affect thyroid hormones and tsh by various mechanisms and those examples are diazepam, ethioamide, lovastatin, metoclopramide, 6-mercaptopurine, nitroprusside, perphenazine, and thiazide diuretics. some drugs may cause a transient decrease in tsh secretion without hypothyroidism and those drugs (dose) are dopamine (greater than 1 mcg per kg per min), glucocorticoids (hydrocortisone greater than 100 mg per day or equivalent) and octreotide (greater than 100 mcg per day). 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. 12.3 pharmacokinetics absorption – levothyroxine sodium for injection is administered via the intravenous route. following administration, the synthetic levothyroxine cannot be distinguished from the natural hormone that is secreted endogenously. 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 t 4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of t 4 compared to t 3 . 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 warnings and precautions ( 5 ) and drug interactions ( 7 )]. thyroid hormones do not readily cross the placental barrier [ see warnings and precautions ( 5 ) and use in specific populations ( 8 )]. metabolism – t 4 is slowly eliminated. the major pathway of thyroid hormone metabolism is through sequential deiodination. approximately eighty percent of circulating t 3 is derived from peripheral t 4 by monodeiodination. the liver is the major site of degradation for both t 4 and t 3 , with t 4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. approximately 80% of the daily dose of t 4 is deiodinated to yield equal amounts of t 3 and reverse t 3 (r t 3 ). t 3 and r t 3 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. elimination – 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 t 4 decreases with age. table 1: pharmacokinetic parameters of thyroid hormones in euthyroid patients hormone ratio in thyroglobulin biologic potency half-life (days) protein binding (%) 2 t 4 10 - 20 1 6 - 8 1 99.96 t 3 1 4 ≤ 2 99.5 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. drug interactions a listing of drug interaction with t 4 is provided in the following tables, although it 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 : drugs that may alter t 4 and t 3 serum transport without affecting free t 4 concentration (euthyroidism) drugs that may increase serum tbg concentration drugs that may decrease serum tbg concentration clofibrate estrogen-containing oral contraceptives estrogens (oral) heroin/ methadone 5-fluorouracil mitotane tamoxifen androgens / anabolic steroids asparaginase glucocorticoids slow-release nicotinic acid drugs that may cause protein-binding site displacement potential impact: 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 and, therefore, patients are clinically euthyroid. salicylates (> 2g/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: furosemide (>80 mg iv) heparin hydantoins non-steroidal anti-inflammatory drugs - fenamates - phenylbutazone table 3: 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 increase levothyroxine requirements. drug or drug class carbamazepine hydantoins phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-t 4 may be reduced by 20% to 40%, but most patients have normal serum tsh levels and are clinically euthyroid. other drugs: phenobarbital rifampin table 4: 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 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 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 drug: amiodarone