Levothyroxine Sodium

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Levothyroxine Sodium

Overview

What is Levothyroxine Sodium?

Levothyroxine sodium tablets, USP contain synthetic crystalline L-3,3’,5,5’-tetraiodothyronine sodium salt [levothyroxine (T) sodium]. Synthetic T is identical to that produced in the human thyroid gland. Levothyroxine (T) sodium has a molecular formula of CHIN NaO* HO, molecular weight of 798.86 g/mol (anhydrous), and structural formula as shown:

What does Levothyroxine Sodium look like?

What are the available doses of Levothyroxine Sodium?

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What should I talk to my health care provider before I take Levothyroxine Sodium?

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How should I use Levothyroxine Sodium?

Levothyroxine sodium is used for the following indications:

The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of levothyroxine sodium tablets that is adequate to achieve these goals depends on a variety of factors including the patient’s age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated (see and ). Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters (see ).

Levothyroxine sodium tablets should be taken in the morning on an empty stomach, at least one-half hour before any food is eaten. Levothyroxine sodium tablets should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see ).

Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4 to 6 weeks.

Caution should be exercised when administering levothyroxine sodium tablets to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see ).

What interacts with Levothyroxine Sodium?

What are the warnings of Levothyroxine Sodium?

There have been rare, but serious, reports of arrhythmias associated with the use of sodium phosphate products. OsmoPrep should be used with caution in patients with higher risk of arrhythmias (patients with a history of cardiomyopathy, patients with prolonged QT, patients with a history of uncontrolled arrhythmias, and patients with a recent history of a myocardial infarction). Pre-dose and post-colonoscopy ECGs should be considered in patients with high risk of serious, cardiac arrhythmias.

Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.

In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis (see ). If the serum TSH level is not suppressed, levothyroxine should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.

What are the precautions of Levothyroxine Sodium?

General

Levothyroxine has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or under-treatment. These consequences include, among others, effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Many drugs interact with levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response (see ).

Effects on Bone Mineral Density

In women, long-term levothyroxine sodium therapy has been associated with increased bone resorption, thereby decreasing bone mineral density, especially in postmenopausal women on greater than replacement doses or in women who are receiving suppressive doses of levothyroxine sodium. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase and suppressed serum parathyroid hormone levels. Therefore, it is recommended that patients receiving levothyroxine sodium be given the minimum dose necessary to achieve the desired clinical and biochemical response.

Patients with Underlying Cardiovascular Disease

Exercise caution when administering levothyroxine to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease. In these patients, levothyroxine therapy should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease (see ; ; and ). If cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and then cautiously restarted at a lower dose. Overtreatment with levothyroxine sodium may have adverse cardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias. Patients with coronary artery disease who are receiving levothyroxine therapy should be monitored closely during surgical procedures, since the possibility of precipitating cardiac arrhythmias may be greater in those treated with levothyroxine. Concomitant administration of levothyroxine and sympathomimetic agents to patients with coronary artery disease may precipitate coronary insufficiency.

Patients with Nontoxic Diffuse Goiter or Nodular Thyroid Disease

Exercise caution when administering levothyroxine to patients with nontoxic diffuse goiter or nodular thyroid disease in order to prevent precipitation of thyrotoxicosis (see WARNINGS). If the serum TSH is already suppressed, levothyroxine sodium should not be administered (see CONTRAINDICATIONS).

Associated Endocrine Disorders

Hypothalamic/Pituitary Hormone Deficiencies

In patients with secondary or tertiary hypothyroidism, additional hypothalamic/pituitary hormone deficiencies should be considered, and, if diagnosed, treated (see ).

Autoimmune Polyglandular Syndrome

Occasionally, chronic autoimmune thyroiditis may occur in association with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus. Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of treatment with levothyroxine sodium. Failure to do so may precipitate an acute adrenal crisis when thyroid hormone therapy is initiated, due to increased metabolic clearance of glucocorticoids by thyroid hormone. Patients with diabetes mellitus may require upward adjustments of their antidiabetic therapeutic regimens when treated with levothyroxine (see ).

Other Associated Medical Conditions

Infants with congenital hypothyroidism appear to be at increased risk for other congenital anomalies, with cardiovascular anomalies (pulmonary stenosis, atrial septal defect, and ventricular septal defect) being the most common association.

Information for Patients

Patients should be informed of the following information to aid in the safe and effective use of levothyroxine sodium:

Laboratory Tests

General

The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation assay sensitivity ≤ 0.1 mIU/L or third generation assay sensitivity ≤ 0.01 mIU/L) and measurement of free-T.

The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. The choice of laboratory tests depends on various factors including the etiology of the underlying thyroid disease, the presence of concomitant medical conditions, including pregnancy, and the use of concomitant medications (see and ). Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of levothyroxine sodium may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T potency of the drug product.

Adults

In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6 to 8 week intervals until normalization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after 8 to 12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6 to 12 months, depending on the clinical situation, and whenever there is a change in the patient’s status. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving levothyroxine sodium (see , , and ).

Pediatrics

In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring both serum TSH (using a sensitive assay) and total- or free-T. During the first 3 years of life, the serum total- or free-T should be maintained at all times in the upper half of the normal range. While the aim of therapy is to also normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid feedback threshold as a result of hypothyroidism. Failure of the serum T to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium therapy and/or of the serum TSH to decrease below 20 mU/L within 4 weeks should alert the physician to the possibility that the child is not receiving adequate therapy. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of levothyroxine sodium.

The recommended frequency of monitoring of TSH and total or free T in children is as follows: at 2 and 4 weeks after the initiation of treatment; every 1 to 2 months during the first year of life; every 2 to 3 months between 1 and 3 years of age; and every 3 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T levels, and a physical examination, if indicated, be performed 2 weeks after any change in levothyroxine sodium dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals (see and ).

Secondary (Pituitary) and Tertiary (Hypothalamic) Hypothyroidism

Adequacy of therapy should be assessed by measuring serum free-T levels, which should be maintained in the upper half of the normal range in these patients.

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. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs. A listing of drug-thyroidal axis interactions is contained in Table 2.

The list of drug-thyroidal axis interactions in Table 2 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: Drug-Thyroidal Axis Interactions**
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine AgonistsGlucocorticoidsOctreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion	Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
AminoglutethimideAmiodaroneIodide (including iodine-containing radiographic contrast agents)LithiumMethimazolePropylthiouracil (PTU)SulfonamidesTolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T and Tlevels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
AmiodaroneIodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T absorption, which may result in hypothyroidism
Antacids- Aluminum & Magnesium Hydroxides- SimethiconeBile Acid Sequestrants- Cholestyramine- ColestipolCalcium CarbonateCation Exchange Resins- KayexalateFerrous SulfateOrlistatSucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T and T serum transport - but FT concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
ClofibrateEstrogen-containing oral contraceptivesEstrogens (oral)Heroin/Methadone5-FluorouracilMitotaneTamoxifen	Androgens/Anabolic SteroidsAsparaginaseGlucocorticoidsSlow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)HeparinHydantoinsNon-Steroidal Anti-Inflammatory Drugs- Fenamates- PhenylbutazoneSalicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%.
Drugs that may alter T and T metabolism	Drugs that may increase hepatic metabolism, which may result in hypothyroidism
CarbamazepineHydantoinsPhenobarbitalRifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 5'-deiodinase activity
AmiodaroneBeta-adrenergic antagonists- (e.g., Propranolol > 160 mg/day)Glucocorticoids- (e.g., Dexamethasone ³ 4 mg/day)Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T to T, leading to decreased T levels. However, serum Tlevels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T and T 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. Short-term administration of large doses of glucocorticoids may decrease serum Tconcentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and Tlevels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)- Coumarin Derivatives- Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants- Tricyclics (e.g., Amitriptyline)- Tetracyclics (e.g., Maprotiline)- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic 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 arrhythmiasand CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents- Biguanides- Meglitinides- Sulfonylureas- Thiazolidinediones- Insulin	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.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines- Interferon-α- Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones- Somatrem- Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators- (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of I, I, and Tc.
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.
Chloral HydrateDiazepamEthionamideLovastatinMetoclopramide6-MercaptopurineNitroprussidePara-aminosalicylate sodiumPerphenazineResorcinol (excessive topical use)Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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 dose is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see ).

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 (see ).

Drug-Food Interactions

Consumption of certain foods may affect levothyroxine absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the GI tract.

Drug-Laboratory Test Interactions

Changes in TBG concentration must be considered when interpreting T and T values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free T index (FTI). 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 (see also ). Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine. The synthetic T in levothyroxine sodium is identical to that produced naturally by the human thyroid gland. Although there has been a reported association between prolonged thyroid hormone therapy and breast cancer, this has not been confirmed. Patients receiving levothyroxine sodium for appropriate clinical indications should be titrated to the lowest effective replacement dose.

Pregnancy

Teratogenic Effects. Pregnancy Category A

Studies in women taking levothyroxine sodium during pregnancy have not shown an increased risk of congenital abnormalities. Therefore, the possibility of fetal harm appears remote. Levothyroxine sodium should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, pre-eclampsia, stillbirth and premature delivery. Maternal hypothyroidism may have an adverse effect on fetal and childhood growth and development. During pregnancy, serum T levels may decrease and serum TSH levels increase to values outside the normal range. Since elevations in serum TSH may occur as early as 4 weeks gestation, pregnant women taking levothyroxine sodium should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of levothyroxine sodium. Since postpartum TSH levels are similar to preconception values, the levothyroxine sodium dosage should return to the pre-pregnancy dose immediately after delivery. A serum TSH level should be obtained 6 to 8 weeks postpartum.

Thyroid hormones cross the placental barrier to some extent as evidenced by levels in cord blood of athyreotic fetuses being approximately one-third maternal levels. Transfer of thyroid hormone from the mother to the fetus, however, may not be adequate to prevent hypothyroidism.

Nursing Mothers

Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when levothyroxine sodium is administered to a nursing woman. However, adequate replacement doses of levothyroxine are generally needed to maintain normal lactation.

Pediatric Use

General

The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development.

The initial dose of levothyroxine varies with age and body weight (see ). Dosing adjustments are based on an assessment of the individual patient’s clinical and laboratory parameters (see ).

In children in whom a diagnosis of permanent hypothyroidism has not been established, it is recommended that levothyroxine administration be discontinued for a 30-day trial period, but only after the child is at least 3 years of age. Serum T and TSH levels should then be obtained. If the T is low and the TSH high, the diagnosis of permanent hypothyroidism is established, and levothyroxine therapy should be reinstituted. If the T and TSH levels are normal, euthyroidism may be assumed and, therefore, the hypothyroidism can be considered to have been transient. In this instance, however, the physician should carefully monitor the child and repeat the thyroid function tests if any signs or symptoms of hypothyroidism develop. In this setting, the clinician should have a high index of suspicion of relapse. If the results of the levothyroxine withdrawal test are inconclusive, careful follow-up and subsequent testing will be necessary.

Since some more severely affected children may become clinically hypothyroid when treatment is discontinued for 30 days, an alternate approach is to reduce the replacement dose of levothyroxine by half during the 30-day trial period. If, after 30 days, the serum TSH is elevated above 20 mU/L, the diagnosis of permanent hypothyroidism is confirmed, and full replacement therapy should be resumed. However, if the serum TSH has not risen to greater than 20 mU/L, levothyroxine treatment should be discontinued for another 30-day trial period followed by repeat serum T and TSH testing.

The presence of concomitant medical conditions should be considered in certain clinical circumstances and, if present, appropriately treated (see ).

Congenital Hypothyroidism

(see and )

Rapid restoration of normal serum T concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, levothyroxine sodium therapy should be initiated immediately upon diagnosis and is generally continued for life.

During the first 2 weeks of levothyroxine sodium therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration from avid suckling.

The patient should be monitored closely to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment has been associated with craniosynostosis in infants, and may adversely affect the tempo of brain maturation and accelerate the bone age with resultant premature closure of the epiphyses and compromised adult stature.

Acquired Hypothyroidism in Pediatric Patients

The patient should be monitored closely to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height.

Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, levothyroxine therapy should not be initiated at the full replacement dose (see , , and ).

What are the side effects of Levothyroxine Sodium?

Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage (see and ). They include the following:

General:

Central Nervous System:

Musculoskeletal:

Cardiovascular:

Respiratory:

Gastrointestinal:

Dermatologic:

Endocrine:

Reproductive:

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.

Seizures have been reported rarely with the institution of levothyroxine therapy.

Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism.

Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

What should I look out for while using Levothyroxine Sodium?

What might happen if I take too much Levothyroxine Sodium?

The signs and symptoms of overdosage are those of hyperthyroidism (see and ). In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures have occurred in a child ingesting 18 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

How should I store and handle Levothyroxine Sodium?

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from light.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from light.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from light.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Levothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central PharmacyLevothyroxine Sodium Tablets, USP are available as capsule-shaped tablets that are debossed with an on one side of the tablet. The other side of each tablet is debossed with an to the left of the score and an individual tablet identification number to the right of the score. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.U.S. Patent No. 6,645,526U.S. Patent No. 6,936,274U.S. Patent No. 7,052,717U.S. Patent No. 7,195,779Mylan Pharmaceuticals Inc.Morgantown, WV 26505This Product was Repackaged By:State of Florida DOH Central Pharmacy

Clinical Information

Chemical Structure

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Clinical Pharmacology

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, L-thyroxine (T) and L-triiodothyronine (T), by the thyroid gland. Circulating serum T and T levels exert a feedback effect on both TRH and TSH secretion. When serum T and T levels increase, TRH and TSH secretion decrease. When thyroid hormone levels decrease, TRH and TSH secretion increase.

The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T and T 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.

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.

The physiological actions of thyroid hormones are produced predominantly by T, the majority of which (approximately 80%) is derived from T by deiodination in peripheral tissues.

Levothyroxine, at doses individualized according to patient response, is effective as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.

Levothyroxine is also effective in the suppression of pituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimoto’s thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropin-dependent well differentiated thyroid cancer (see , , and ).

Non-Clinical Toxicology

Levothyroxine sodium tablets are contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T and T levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids (see ). Levothyroxine sodium is contraindicated in patients with hypersensitivity to any of the inactive ingredients in levothyroxine sodium tablets. (See .)

Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.

In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis (see ). If the serum TSH level is not suppressed, levothyroxine should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.

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. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs. A listing of drug-thyroidal axis interactions is contained in Table 2.

The list of drug-thyroidal axis interactions in Table 2 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.

Levothyroxine has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or under-treatment. These consequences include, among others, effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Many drugs interact with levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response (see ).

Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage (see and ). They include the following:

General:

Central Nervous System:

Musculoskeletal:

Cardiovascular:

Respiratory:

Gastrointestinal:

Dermatologic:

Endocrine:

Reproductive:

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.

Seizures have been reported rarely with the institution of levothyroxine therapy.

Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism.

Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

Review

Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

Tips

Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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