Levothyroxine Interactions

7 DRUG INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium. (7) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on 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 (Tables 5 to 8). Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Phosphate Binders (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum) Phosphate binders may bind to levothyroxine. Administer levothyroxine sodium tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and levothyroxine sodium for changes in thyroid function. Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol) Ion Exchange Resins (e.g., Kayexalate) Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels. Proton Pump Inhibitors Sucralfate Antacids (e.g., 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 6. 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 levothyroxine sodium 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 7. 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 levothyroxine sodium 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 8. 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 levothyroxine sodium 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 Levothyroxine sodium 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 levothyroxine sodium dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides Levothyroxine sodium 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 levothyroxine sodium 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 sodium may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium may result in increased levothyroxine sodium requirements. 7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and levothyroxine sodium 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 levothyroxine sodium 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 levothyroxine sodium from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. 7.10 Drug-Laboratory Test Interactions Thyroxine-binding Globulin (TBG) 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. Biotin Biotin supplementation is known to interfere with thyroid hormone immunoassays that are based on a biotin and streptavidin interaction, which may result in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days prior to thyroid testing.

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on 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 (Tables 5 to 8). Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Phosphate Binders (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum) Phosphate binders may bind to levothyroxine. Administer levothyroxine sodium tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and levothyroxine sodium for changes in thyroid function. Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol) Ion Exchange Resins (e.g., Kayexalate) Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels. Proton Pump Inhibitors Sucralfate Antacids (e.g., 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 6. 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 levothyroxine sodium 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 7. 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 levothyroxine sodium 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 8. 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 levothyroxine sodium 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 Levothyroxine sodium 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 levothyroxine sodium dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

7.4 Digitalis Glycosides Levothyroxine sodium 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 levothyroxine sodium 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 sodium may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium may result in increased levothyroxine sodium requirements.

7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

7.7 Sympathomimetics Concurrent use of sympathomimetics and levothyroxine sodium 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 DRUG INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium Tablets. ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on 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 Tablets (see Tables 2-5 below). Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of Levothyroxine Sodium Tablets by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Calcium Carbonate Ferrous Sulfate Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer Levothyroxine Sodium Tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and Levothyroxine Sodium Tablets 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 Levothyroxine Sodium Tablets 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 Levothyroxine Sodium Tablets results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. Salicylates (greater than 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 (greater than 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 Levothyroxine Sodium Tablets 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 greater than 160 mg/day) In patients treated with large doses of propranolol (greater than 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 greater than or equal to 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 Levothyroxine Sodium Tablets 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 Levothyroxine Sodium Tablets increase 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 Levothyroxine Sodium Tablets dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides Levothyroxine Sodium Tablets 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 Levothyroxine Sodium Tablets 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 Sodium Tablets may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on Levothyroxine Sodium Tablets may result in increased Levothyroxine Sodium Tablets requirements. 7.6 Ketamine Concurrent use of ketamine and Levothyroxine Sodium Tablets may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and Levothyroxine Sodium Tablets 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 Levothyroxine Sodium Tablets 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 Levothyroxine Sodium Tablets 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.

7 DRUG INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium tablets. (7) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on 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 tablets (see Tables 2-5 below). Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium tablets by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Calcium Carbonate Ferrous Sulfate Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine sodium tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 Levothyroxine sodium tablets 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 levothyroxine sodium tablets dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides Levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 sodium tablets may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium tablets may result in increased levothyroxine sodium tablets requirements. 7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium tablets may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets 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.

7 DRUG INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium tablets. ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on 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 tablets (Tables 5 to 8). Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium tablets by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Phosphate Binders (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum) Phosphate binders may bind to levothyroxine. Administer levothyroxine sodium tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and levothyroxine sodium tablets for changes in thyroid function. Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol) Ion Exchange Resins (e.g., Kayexalate) Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels. Proton Pump Inhibitors Sucralfate Antacids (e.g., 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 6. 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 levothyroxine sodium tablets 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 7. 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 levothyroxine sodium tablets 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 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 8. 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 levothyroxine sodium tablets 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 Levothyroxine sodium tablet 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 levothyroxine sodium tablets dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides Levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 sodium tablets may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium tablets may result in increased levothyroxine sodium tablets requirements. 7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium tablets may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. 7.10 Drug-Laboratory Test Interactions Thyroxine-binding Globulin (TBG) 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. Biotin Biotin supplementation is known to interfere with thyroid hormone immunoassays that are based on a biotin and streptavidin interaction, which may result in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days prior to thyroid testing.

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