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| Product NDC Code | 70860-452 | ||||
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| Drug Name | Levothyroxine sodium |
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| Type | Brand | ||||
| Pharm Class | Thyroxine [CS], l-Thyroxine [EPC] |
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| Active Ingredients |
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| Route | INTRAVENOUS | ||||
| Dosage Form | INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION | ||||
| RxCUI drug identifier | 966219, 1115267, 1115269 |
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| Application Number | ANDA208749 | ||||
| Labeler Name | Athenex Pharmaceutical Division, LLC. | ||||
| Packages |
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| Check if available Online | Get Medication Prices online with Discount |
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 for Injection (greater than 500 mcg) are associated with cardiac complications in patients with underlying cardiac disease. Treatment of Overdosage Levothyroxine Sodium for 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 Excessive doses of levothyroxine can predispose to signs and symptoms compatible with hyperthyroidism. The signs and symptoms of thyrotoxicosis include, but are not limited to: exophthalmic goiter, weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, angina pectoris, tremors, insomnia, heat intolerance, fever, and menstrual irregularities. Excessive doses of L-thyroxine can predispose to signs and symptoms compatible with hyperthyroidism. To report SUSPECTED ADVERSE REACTIONS, contact Athenex Pharmaceutical Division, LLC. at 1-855-273-0154 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Drug and or laboratory test interactions
Information about any known interference by the drug with laboratory tests.7.7 Drug-Laboratory Test Interactions Changes in thyroxine binding globulin (TBG) concentration must be considered when interpreting levothyroxine and triiodothyronine values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free levothyroxine index. Pregnancy, infectious hepatitis, estrogens, estrogen containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or corticosteroid therapy. Familial hyper or hypo thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.
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., synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium for Injection. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs [see Pharmacokinetics ( 12.3 )]. Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium for Injection. ( 7 , 12.3 ) 7.1 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, especially when thyroid therapy is started, changed, or discontinued. 7.2 Oral Anticoagulants Levothyroxine increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the Levothyroxine Sodium for Injection dose is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments. 7.3 Digitalis Glycosides The therapeutic effects of digitalis glycosides may be reduced by levothyroxine. Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. 7.4 Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. 7.5 Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. 7.6 Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. 7.7 Drug-Laboratory Test Interactions Changes in thyroxine binding globulin (TBG) concentration must be considered when interpreting levothyroxine and triiodothyronine values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free levothyroxine index. Pregnancy, infectious hepatitis, estrogens, estrogen containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or corticosteroid therapy. Familial hyper or hypo thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 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, ethionamide, lovastatin, metoclopramide, 6-mercaptopurine, nitroprusside, perphenazine, and thiazide diuretics. Some drugs may cause a transient decrease in TSH secretion without hypothyroidism and those drugs (dose) are dopamine (greater than 1 mcg per kg per min), glucocorticoids (hydrocortisone greater than 100 mg per day or equivalent) and octreotide (greater than 100 mcg per day). Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development. 12.3 Pharmacokinetics Absorption – Levothyroxine Sodium for Injection is administered via the intravenous route. Following administration, the synthetic levothyroxine cannot be distinguished from the natural hormone that is secreted endogenously. Distribution – Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine binding globulin (TBG), thyroxine binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T 4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T 4 compared to T 3 . Protein bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins [see Warnings and Precautions ( 5 ) and Drug Interactions ( 7 )]. Thyroid hormones do not readily cross the placental barrier [see Warnings and Precautions ( 5 ) and Use in Specific Populations ( 8 )]. Metabolism – T 4 is slowly eliminated. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately eighty percent of circulating T 3 is derived from peripheral T 4 by monodeiodination. The liver is the major site of degradation for both T 4 and T 3 , with T 4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T 4 is deiodinated to yield equal amounts of T 3 and reverse T 3 (r T 3 ). T 3 and r T 3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation. Elimination – Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged, where it is hydrolyzed and eliminated in feces as the free hormones. Urinary excretion of T 4 decreases with age. Table 1: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency Half-Life (Days) Protein Binding (%) 2 T 4 : Levothyroxine T 3 : Liothyronine 1 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism. 2 Includes TBG, TBPA, and TBA. T 4 10 to 20 1 6 to 8 1 99.96 T 3 1 4 ≤ 2 99.5 Drug Interactions A listing of drug interaction with T 4 is provided in the following tables, although it may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware of this fact and should consult appropriate reference sources (e.g., package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected. Table 2: Drugs That May Alter T 4 and T 3 Serum Transport Without Affecting free T 4 Concentration (Euthyroidism) Drugs That May Increase Serum TBG Concentration Drugs That May Decrease Serum TBG Concentration Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid Drugs That May Cause Protein-Binding Site Displacement Potential impact: Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates (>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: Furosemide (>80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates - Phenylbutazone Table 3: Drugs That May Alter Hepatic Metabolism of T 4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Drug or Drug Class Carbamazepine Hydantoins Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Other drugs: Phenobarbital Rifampin Table 4: Drugs That May Decrease Conversion of T 4 to T 3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3 , leading to decreased T 3 levels. However, serum 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 drug: Amiodarone
| T 4 | 10 to 20 | 1 | 6 to 8 1 | 99.96 |
| T 3 | 1 | 4 | ≤ 2 | 99.5 |
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen | Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
| Potential impact: Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4and normal FT 4and TSH concentrations and, therefore, patients are clinically euthyroid. | |
| Salicylates (>2 g/day) | Salicylates inhibit binding of T 4and T 3to TBG and transthyretin. An initial increase in serum FT 4is followed by return of FT 4to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4levels may decrease by as much as 30%. |
| Other drugs: Furosemide (>80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates - Phenylbutazone | |
| Carbamazepine Hydantoins | Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T 4may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
| Other drugs: Phenobarbital Rifampin | |
| Beta-adrenergic antagonists (e.g., Propranolol >160 mg/day) | In patients treated with large doses of propranolol (>160 mg/day), T 3and T 4levels 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 3concentrations by 30% with minimal change in serum T 4levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3and T 4levels due to decreased TBG production (see above). |
| Other drug: Amiodarone | |
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, ethionamide, 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 for Injection is administered via the intravenous route. Following administration, the synthetic levothyroxine cannot be distinguished from the natural hormone that is secreted endogenously. Distribution – Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine binding globulin (TBG), thyroxine binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T 4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T 4 compared to T 3 . Protein bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins [see Warnings and Precautions ( 5 ) and Drug Interactions ( 7 )]. Thyroid hormones do not readily cross the placental barrier [see Warnings and Precautions ( 5 ) and Use in Specific Populations ( 8 )]. Metabolism – T 4 is slowly eliminated. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately eighty percent of circulating T 3 is derived from peripheral T 4 by monodeiodination. The liver is the major site of degradation for both T 4 and T 3 , with T 4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T 4 is deiodinated to yield equal amounts of T 3 and reverse T 3 (r T 3 ). T 3 and r T 3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation. Elimination – Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged, where it is hydrolyzed and eliminated in feces as the free hormones. Urinary excretion of T 4 decreases with age. Table 1: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency Half-Life (Days) Protein Binding (%) 2 T 4 : Levothyroxine T 3 : Liothyronine 1 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism. 2 Includes TBG, TBPA, and TBA. T 4 10 to 20 1 6 to 8 1 99.96 T 3 1 4 ≤ 2 99.5 Drug Interactions A listing of drug interaction with T 4 is provided in the following tables, although it may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware of this fact and should consult appropriate reference sources (e.g., package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected. Table 2: Drugs That May Alter T 4 and T 3 Serum Transport Without Affecting free T 4 Concentration (Euthyroidism) Drugs That May Increase Serum TBG Concentration Drugs That May Decrease Serum TBG Concentration Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid Drugs That May Cause Protein-Binding Site Displacement Potential impact: Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates (>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: Furosemide (>80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates - Phenylbutazone Table 3: Drugs That May Alter Hepatic Metabolism of T 4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Drug or Drug Class Carbamazepine Hydantoins Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Other drugs: Phenobarbital Rifampin Table 4: Drugs That May Decrease Conversion of T 4 to T 3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3 , leading to decreased T 3 levels. However, serum 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 drug: Amiodarone
| T 4 | 10 to 20 | 1 | 6 to 8 1 | 99.96 |
| T 3 | 1 | 4 | ≤ 2 | 99.5 |
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen | Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
| Potential impact: Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4and normal FT 4and TSH concentrations and, therefore, patients are clinically euthyroid. | |
| Salicylates (>2 g/day) | Salicylates inhibit binding of T 4and T 3to TBG and transthyretin. An initial increase in serum FT 4is followed by return of FT 4to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4levels may decrease by as much as 30%. |
| Other drugs: Furosemide (>80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates - Phenylbutazone | |
| Carbamazepine Hydantoins | Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T 4may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
| Other drugs: Phenobarbital Rifampin | |
| Beta-adrenergic antagonists (e.g., Propranolol >160 mg/day) | In patients treated with large doses of propranolol (>160 mg/day), T 3and T 4levels 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 3concentrations by 30% with minimal change in serum T 4levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3and T 4levels due to decreased TBG production (see above). |
| Other drug: Amiodarone | |
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 for Injection contains synthetic crystalline 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 for Injection is a sterile, preservative-free lyophilized powder consisting of the active ingredient, levothyroxine sodium, and the excipients dibasic sodium phosphate heptahydrate; mannitol; and sodium hydroxide, in single-dose amber glass vials. Levothyroxine Sodium for Injection is available at three dosage strengths: 100 mcg per vial, 200 mcg per vial, and 500 mcg per vial. Structural Formula
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 An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg followed by once daily intravenous maintenance doses between 50 and 100 mcg should be administered, as clinically indicated, until the patient can tolerate oral therapy. ( 2.1 ) Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP. Shake vial to ensure complete mixing. Reconstituted drug product is preservative free. Use immediately after reconstitution. Discard any unused portion. ( 2.3 ) Do not add to other IV fluids. ( 2.3 ) 2.1 Dosage An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy. The age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium for Injection. Levothyroxine Sodium for 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 for 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 for Injection and oral levothyroxine products has not been established. Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium for Injection is estimated to be from 48 to 74%. Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly. 2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease Intravenous levothyroxine may be associated with cardiac toxicity-including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death in the elderly and in those with underlying cardiovascular disease. Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations. 2.3 Reconstitution Directions Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only. Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL, 40 mcg per mL, and 100 mcg per mL for the 100 mcg, 200 mcg, and 500 mcg vials, respectively. Reconstituted drug product is preservative free and is stable for 4 hours. Discard any unused portion. DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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 for Injection is supplied as a lyophilized powder at three strengths in single-dose amber-colored vials: 100 mcg, 200 mcg, and 500 mcg. Lyophilized powder for injection in single-dose vials: 100 mcg, 200 mcg, and 500 mcg. ( 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 for Injection is indicated for the treatment of myxedema coma. Important Limitations of Use: The relative bioavailability between Levothyroxine Sodium for Injection and oral levothyroxine products has not been established. Caution should be used when switching patients from oral levothyroxine products to Levothyroxine Sodium for Injection as accurate dosing conversion has not been studied. Levothyroxine Sodium is an L-thyroxine product. Levothyroxine (T 4 ) Sodium for 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.
Spl product data elements
Usually a list of ingredients in a drug product.Levothyroxine Sodium levothyroxine sodium anhydrous MANNITOL SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE SODIUM HYDROXIDE LEVOTHYROXINE SODIUM ANHYDROUS LEVOTHYROXINE Levothyroxine Sodium levothyroxine sodium anhydrous MANNITOL SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE SODIUM HYDROXIDE LEVOTHYROXINE SODIUM ANHYDROUS LEVOTHYROXINE Levothyroxine Sodium levothyroxine sodium anhydrous MANNITOL SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE SODIUM HYDROXIDE LEVOTHYROXINE SODIUM ANHYDROUS LEVOTHYROXINE
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and Pharmacology No animal toxicology studies have been conducted with Levothyroxine Sodium for Injection.
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 for 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 for Injection. 13.2 Animal Toxicology and Pharmacology No animal toxicology studies have been conducted with Levothyroxine Sodium for 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.PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label NDC 70860-451-10 Levothyroxine Sodium for Injection 100 mcg per vial Rx only For Intravenous Use Single-Dose Vial Discard any unused portion PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label NDC 70860-452-10 Levothyroxine Sodium for Injection 200 mcg per vial Rx only For Intravenous Use Single-Dose Vial Discard any unused portion PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label NDC 70860-453-10 Levothyroxine Sodium for Injection 500 mcg per vial Rx only For Intravenous Use Single-Dose Vial Discard any unused portion PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
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 for 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 Labor and Delivery Patients in labor who develop myxedema have not been reported in the literature. However, patients should be treated with Levothyroxine Sodium for Injection as the risk of non-treatment is associated with a high probability of significant morbidity or mortality to the maternal patient and the fetus.
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.3 Nursing Mothers Adequate replacement doses of thyroid hormones are required to maintain normal lactation. There are no reported cases of Levothyroxine Sodium for Injection used to treat myxedema coma in patients who are lactating. However, such patients should be treated with Levothyroxine Sodium for Injection as the risk of nontreatment is associated with a high probability of significant morbidity or mortality to the nursing patient.
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 Myxedema coma is a disease of the elderly. An approved, oral dosage form of levothyroxine should be used in the pediatric patient population for maintaining a euthyroid state in non-complicated hypothyroidism.
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 Pregnancy Category A – There are no reported cases of Levothyroxine Sodium for Injection used to treat myxedema coma in patients who were pregnant or lactating. Studies in pregnant women treated with oral levothyroxine to maintain a euthyroid state have not shown an increased risk of fetal abnormalities. Therefore, pregnant patients who develop myxedema should be treated with Levothyroxine Sodium for Injection as the risk of non-treatment is associated with a high probability of significant morbidity or mortality to the maternal patient and 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 Pregnancy Category A – There are no reported cases of Levothyroxine Sodium for Injection used to treat myxedema coma in patients who were pregnant or lactating. Studies in pregnant women treated with oral levothyroxine to maintain a euthyroid state have not shown an increased risk of fetal abnormalities. Therefore, pregnant patients who develop myxedema should be treated with Levothyroxine Sodium for Injection as the risk of non-treatment is associated with a high probability of significant morbidity or mortality to the maternal patient and the fetus. 8.2 Labor and Delivery Patients in labor who develop myxedema have not been reported in the literature. However, patients should be treated with Levothyroxine Sodium for Injection as the risk of non-treatment is associated with a high probability of significant morbidity or mortality to the maternal patient and the fetus. 8.3 Nursing Mothers Adequate replacement doses of thyroid hormones are required to maintain normal lactation. There are no reported cases of Levothyroxine Sodium for Injection used to treat myxedema coma in patients who are lactating. However, such patients should be treated with Levothyroxine Sodium for Injection as the risk of nontreatment is associated with a high probability of significant morbidity or mortality to the nursing patient. 8.4 Pediatric Use Myxedema coma is a disease of the elderly. An approved, oral dosage form of levothyroxine should be used in the pediatric patient population for maintaining a euthyroid state in non-complicated hypothyroidism. 8.5 Geriatric Use and Patients with Underlying Cardiovascular Disease See Section 2, Dosage and Administration, for full prescribing information in the geriatric patient population. Because of the increased prevalence of cardiovascular disease in the elderly, cautious use of Levothyroxine Sodium for Injection in the elderly and in patients with known cardiac risk factors is advised. Atrial fibrillation is a common side effect associated with levothyroxine treatment in the elderly [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5 )].
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 for Injection is supplied as follows: NDC Levothyroxine Sodium for Injection Reconstituted Concentration Package Factor 70860-451-10 100 mcg Single-Dose Vial 20 mcg per mL 1 vial per carton 70860-452-10 200 mcg Single-Dose Vial 40 mcg per mL 1 vial per carton 70860-453-10 500 mcg Single-Dose Vial 100 mcg per mL 1 vial per carton 16.2 Storage and Handling Store dry product at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light . Discard any unused portion . Sterile, Nonpyrogenic, Preservative-free, Lyophilized. The container closure is not made with natural rubber latex . Athenex Mfd. for Athenex Schaumburg, IL 60173 (USA) Made in India ©2018 Athenex. September 2018
| 70860-451-10 | 100 mcg Single-Dose Vial | 20 mcg per mL | 1 vial per carton |
| 70860-452-10 | 200 mcg Single-Dose Vial | 40 mcg per mL | 1 vial per carton |
| 70860-453-10 | 500 mcg Single-Dose Vial | 100 mcg per mL | 1 vial per carton |
Storage and handling
Information about safe storage and handling of the drug product.16.2 Storage and Handling Store dry product at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light . Discard any unused portion . Sterile, Nonpyrogenic, Preservative-free, Lyophilized. The container closure is not made with natural rubber latex . Athenex Mfd. for Athenex Schaumburg, IL 60173 (USA) Made in India ©2018 Athenex. September 2018
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 for 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 for 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