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| Product NDC Code | 24201-002 | ||||
|---|---|---|---|---|---|
| Drug Name | Levothyroxine sodium |
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| Type | Generic | ||||
| Pharm Class | Thyroxine [CS], l-Thyroxine [EPC] |
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| Active Ingredients |
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| Route | INTRAVENOUS | ||||
| Dosage Form | INJECTION, SOLUTION | ||||
| RxCUI drug identifier | 2621123 | ||||
| Application Number | NDA214253 | ||||
| Labeler Name | Hikma Pharmaceuticals USA Inc. | ||||
| Packages |
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Overdosage of LEVOTHYROXINE SODIUM
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE In general, the signs and symptoms of overdosage with levothyroxine are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Excessive doses of Levothyroxine Sodium Injection (greater than 500 mcg) are associated with cardiac complications in patients with underlying cardiac disease. Treatment of Overdosage Levothyroxine Sodium Injection should be reduced in dose or temporarily discontinued if signs or symptoms of overdosage occur. To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s medical status.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS Adverse reactions associated with levothyroxine are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5) , Overdosage (10) ] . They include the following: General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia Musculoskeletal: tremors, muscle weakness, muscle spasm Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest Respiratory: dyspnea Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests Dermatologic: flushing, rash Seizures have been reported rarely with the institution of levothyroxine therapy. 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. Adverse reactions associated with Levothyroxine Sodium Injection are primarily those of hyperthyroidism due to therapeutic overdosage: 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 Hikma at [email protected] or call 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
LEVOTHYROXINE SODIUM Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium Injection. (7, 12.3) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium Injection (see Tables 1-3). Table 1: Drugs That May Alter T 4 and Triiodothyronine (T 3 ) Serum Transport Without Effecting Free Thyroxine (FT 4 ) 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 Nictonic 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 diabetic 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. 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 9000.
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium Injection (see Tables 1-3). Table 1: Drugs That May Alter T 4 and Triiodothyronine (T 3 ) Serum Transport Without Effecting Free Thyroxine (FT 4 ) 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 Nictonic 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 diabetic 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. 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 9000.
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T 3 ) and levothyroxine (T 4 ) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins. The physiological actions of thyroid hormones are produced predominantly by T 3 , the majority of which (approximately 80%) is derived from T 4 by deiodination in peripheral tissues. 12.2 Pharmacodynamics Thyroid hormone synthesis and secretion is regulated by the hypothalamic pituitary-thyroid axis. Thyrotropin releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin stimulating hormone (TSH) from the anterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, T 4 and T 3 , by the thyroid 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 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)]. Betadex sulfobutyl ether (SBECD) does not affect levothyroxine binding to plasma proteins. 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 mono-deiodination. 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 (rT 3 ). T 3 and rT 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. In patients with severe renal impairment or ESRD (eGFR of < 15 mL/min/1.73 m2), accumulation of SBECD occurs [see Renal Impairment 8.6]. 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 to 20 1 6 to 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.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T 3 ) and levothyroxine (T 4 ) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins. The physiological actions of thyroid hormones are produced predominantly by T 3 , the majority of which (approximately 80%) is derived from T 4 by deiodination in peripheral tissues.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Thyroid hormone synthesis and secretion is regulated by the hypothalamic pituitary-thyroid axis. Thyrotropin releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin stimulating hormone (TSH) from the anterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, T 4 and T 3 , by the thyroid 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.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption – Levothyroxine Sodium 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)]. Betadex sulfobutyl ether (SBECD) does not affect levothyroxine binding to plasma proteins. 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 mono-deiodination. 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 (rT 3 ). T 3 and rT 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. In patients with severe renal impairment or ESRD (eGFR of < 15 mL/min/1.73 m2), accumulation of SBECD occurs [see Renal Impairment 8.6]. 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 to 20 1 6 to 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.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS None None
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Levothyroxine sodium injection contains synthetic levothyroxine (L-thyroxine) sodium salt. Levothyroxine sodium has an empirical formula of C 15 H 10 I 4 NNaO 4 , a molecular weight of 798.85 g/mol (anhydrous), and the following structural formula: Levothyroxine sodium injection is a sterile, preservative-free, clear, colorless to slightly yellow solution for intravenous administration available as 100 mcg/mL in a single-dose clear glass vial. Each mL of levothyroxine sodium injection also contains 0.05 mg arginine, USP; 80 mg betadex sulfobutyl ether sodium, USP; 0.05 mg edetate disodium, USP; and water for injection, USP. Sodium chloride, USP was added to adjust tonicity. Hydrochloric acid, NF and/or sodium hydroxide, NF may have been added for pH adjustment. chemical structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Consider the patient’s age, general physical condition, cardiac risk factors, as well as the clinical severity of myxedema and duration of myxedema symptoms when determining dosages of Levothyroxine Sodium Injection. (2.1) Start with lower doses in elderly patients and in patients with underlying cardiovascular disease. (2.1) An initial intravenous loading dose of Levothyroxine Sodium 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) Do not add to other IV fluids. (2.2) 2.1 Dosage An initial intravenous loading dose of Levothyroxine Sodium 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. The age, general physical condition, and cardiac risk factors of the patient, as well as the clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium Injection. Levothyroxine Sodium Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients. Daily administration of Levothyroxine Sodium Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable. For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state. Relative bioavailability between Levothyroxine Sodium Injection and oral levothyroxine products has not been established. Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium 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 Administration Instructions 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. Discard any unused portion. DO NOT ADD LEVOTHYROXINE SODIUM INJECTION TO OTHER INTRAVENOUS FLUIDS. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
2.1 Dosage An initial intravenous loading dose of Levothyroxine Sodium 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. The age, general physical condition, and cardiac risk factors of the patient, as well as the clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium Injection. Levothyroxine Sodium Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients. Daily administration of Levothyroxine Sodium Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable. For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state. Relative bioavailability between Levothyroxine Sodium Injection and oral levothyroxine products has not been established. Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium 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 Administration Instructions 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. Discard any unused portion. DO NOT ADD LEVOTHYROXINE SODIUM INJECTION TO OTHER INTRAVENOUS FLUIDS. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Levothyroxine sodium injection 100 mcg/mL is a clear, colorless to slightly yellow solution supplied as 1 mL per vial. Injection: 100 mcg/mL in a single-dose vial. Ready-to-use solution. (3)
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Levothyroxine Sodium Injection is indicated for the treatment of myxedema coma. Limitations of Use : The relative bioavailability between Levothyroxine Sodium Injection and oral levothyroxine products has not been established. Caution should be used when switching patients from oral levothyroxine products to Levothyroxine Sodium Injection as accurate dosing conversion has not been studied. Levothyroxine Sodium is an L-thyroxine product. Levothyroxine (T 4 ) Sodium Injection is indicated for the treatment of myxedema coma. (1) Important Limitations of Use: The relative bioavailability of this drug has not been established. Use caution when converting patients from oral to intravenous levothyroxine. (1)
Spl product data elements
Usually a list of ingredients in a drug product.Levothyroxine Sodium LEVOTHYROXINE SODIUM LEVOTHYROXINE SODIUM LEVOTHYROXINE LEVOTHYROXINE SODIUM ARGININE EDETATE DISODIUM BETADEX SULFOBUTYL ETHER SODIUM SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID WATER
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of Levothyroxine Sodium Injection.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of Levothyroxine Sodium Injection. 13.2 Animal Toxicology and Pharmacology No animal toxicology studies have been conducted with Levothyroxine Sodium Injection.
13.2 Animal Toxicology and Pharmacology No animal toxicology studies have been conducted with Levothyroxine Sodium Injection.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.NDC 24201- 002 -01 Levothyroxine Sodium Injection 100 mcg/mL For Intravenous Use 1 mL Single-Dose Vial Discard any unused portion. Rx only carton
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES No clinical studies have been conducted with Levothyroxine Sodium Injection in patients with myxedema coma. However, data from published literature support the intravenous use of levothyroxine sodium for the treatment of myxedema coma.
Labor and delivery
Information about the drug’s use during labor or delivery, whether or not the use is stated in the indications section of the labeling, including the effect of the drug on the mother and fetus, on the duration of labor or delivery, on the possibility of delivery-related interventions, and the effect of the drug on the later growth, development, and functional maturation of the child.8.2 Lactation Risk Summary Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported, and there is no information on the effects of levothyroxine on milk production from levothyroxine oral treatment. There are 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 Sodium Injection and any potential adverse effects on the breastfed infant from Levothyroxine Sodium Injection or from the underlying maternal condition.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and effectiveness of Levothyroxine Sodium Injection have not been established in pediatric patients.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary The clinical data in pregnant women treated with oral levothyroxine to treat hypothyroidism do not indicate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no data available on the use of Levothyroxine Sodium Injection in pregnant women. There are risks to the mother and fetus associated with myxedema coma in pregnancy (see Clinical Considerations) . No developmental or reproductive toxicity studies in animals have been conducted with Levothyroxine Sodium Injection. The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risks of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Myxedema coma is a medical emergency that can be fatal if left untreated. Delaying treatment in pregnant women with myxedema coma increases the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for pregnant women with myxedema coma should not be withheld due to potential concerns regarding the effects of Levothyroxine Sodium Injection on the fetus.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Elderly and those with underlying cardiovascular disease should receive doses at the lower end of the recommended range. (8.5) 8.1 Pregnancy Risk Summary The clinical data in pregnant women treated with oral levothyroxine to treat hypothyroidism do not indicate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no data available on the use of Levothyroxine Sodium Injection in pregnant women. There are risks to the mother and fetus associated with myxedema coma in pregnancy (see Clinical Considerations) . No developmental or reproductive toxicity studies in animals have been conducted with Levothyroxine Sodium Injection. The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risks of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Myxedema coma is a medical emergency that can be fatal if left untreated. Delaying treatment in pregnant women with myxedema coma increases the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for pregnant women with myxedema coma should not be withheld due to potential concerns regarding the effects of Levothyroxine Sodium Injection on the fetus. 8.2 Lactation Risk Summary Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported, and there is no information on the effects of levothyroxine on milk production from levothyroxine oral treatment. There are 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 Sodium Injection and any potential adverse effects on the breastfed infant from Levothyroxine Sodium Injection or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Levothyroxine Sodium Injection have not been established in pediatric patients. 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 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)]. 8.6 Renal Impairment Serum creatinine and levothyroxine levels should be closely monitored in patients with severe renal impairment receiving intravenous levothyroxine with betadex sulfobutyl (SBECD) [See Clinical Pharmacology (12.3)].
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 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)].
8.6 Renal Impairment Serum creatinine and levothyroxine levels should be closely monitored in patients with severe renal impairment receiving intravenous levothyroxine with betadex sulfobutyl (SBECD) [See Clinical Pharmacology (12.3)].
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Levothyroxine Sodium Injection 100 mcg/mL is a clear, colorless to slightly yellow solution, supplied as1 mL per vial. Package of 1 single-dose vial: NDC 24201-002-01 16.2 Storage and Handling Protect from light and store product at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Drug product is preservative free. Discard any unused portion. Manufactured for: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 www.hikma.com/us Revised: 11/2022 INS-0017-R2
16.1 How Supplied Levothyroxine Sodium Injection 100 mcg/mL is a clear, colorless to slightly yellow solution, supplied as1 mL per vial. Package of 1 single-dose vial: NDC 24201-002-01
16.2 Storage and Handling Protect from light and store product at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Drug product is preservative free. Discard any unused portion. Manufactured for: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 www.hikma.com/us Revised: 11/2022 INS-0017-R2
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS Thyroid hormones, including Levothyroxine Sodium Injection, should not be used for the treatment of obesity or for weight loss. (5.3) Larger doses may produce serious or even life-threatening manifestations of toxicity. (6) WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS Thyroid hormones, including Levothyroxine Sodium Injection, should not be used for the treatment of obesity or for weight loss. (5.3) Larger doses may produce serious or even life-threatening manifestations of toxicity. (6)
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API