LEVOTHYROXINE SODIUM- levothyroxine sodium_tablet

Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) 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 T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues. Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as endogenous T4, thereby maintaining normal T4 levels when a deficiency is present. Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%. The majority of the levothyroxine sodium tablets dose is absorbed from the jejunum and upper ileum. The relative bioavailability of levothyroxine sodium tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 99%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption [see Drug Interactions (7)]. 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 T4 partially explains the higher serum levels, slower metabolic clearance and longer half-life of T4 compared to T3. 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 Drug Interactions (7)]. [see Use in Specific Populations (8. T4 is slowly eliminated (see Table 7 Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency t 1/2 Protein Binding (%) a Levothyroxine (T4) 10 - 20 1 6-7 b 99. 96 Liothyronine (T3) 1 4 <= 2 99.

Hypothyroidism Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression Levothyroxine sodium tablets are indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Limitations of Use: Levothyroxine sodium tablets are not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. Levothyroxine sodium tablets is L-thyroxine (T4) indicated for: Limitations of Use:.

Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast. 1) Take levothyroxine sodium tablets with a full glass of water as the tablet may rapidly disintegrate. Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half to one hour before breakfast. [see Drug Interactions (7. 9) and Clinical Pharmacology (12. The dose of levothyroxine sodium tablets for hypothyroidism or pituitary TSH suppression depends on a variety of factors including: the patient's age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food and the specific nature of the condition being treated [see Dosage and Administration (2. 3), Warnings and Precautions (5) and Drug Interactions (7)]. [see Dosage and Administration (2. The peak therapeutic effect of a given dose of levothyroxine sodium tablets may not be attained for 4 to 6 weeks. Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly individuals who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium tablets is approximately 1. 6 mcg per kg per day (for example: 100 to 125 mcg per day for a 70 kg adult). Adjust the dose by 12. 5 to 25 mcg increments every 4 to 6 weeks until the patient is clinically euthyroid and the serum TSH returns to normal. Doses greater than 200 mcg per day are seldom required. An inadequate response to daily doses of greater than 300 mcg per day is rare and may indicate poor compliance, malabsorption, drug interactions or a combination of these factors. For elderly patients or patients with underlying cardiac disease, start with a dose of 12. 5 to 25 mcg per day. Increase the dose every 6 to 8 weeks, as needed until the patient is clinically euthyroid and the serum TSH returns to normal. The full replacement dose of levothyroxine sodium tablets may be less than 1 mcg per kg per day in elderly patients. In patients with severe longstanding hypothyroidism, start with a dose of 12. Adjust the dose in 12. 5 to 25 mcg increments every 2 to 4 weeks until the patient is clinically euthyroid and the serum TSH level is normalized. Secondary or Tertiary Hypothyroidism Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of levothyroxine sodium tablets dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor adequacy of therapy in this patient population. Titrate levothyroxine sodium tablets dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range. Pediatric Dosage - Congenital or Acquired Hypothyroidism The recommended daily dose of levothyroxine sodium tablets in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1 [see Dosage and Administration (2. Levothyroxine Sodium Tablets Dosing Guidelines for Pediatric Hypothyroidism AGE Daily Dose Per Kg Body Weight a 0-3 months 10-15 mcg/kg/day 3-6 months 8-10 mcg/kg/day 6-12 months 6-8 mcg/kg/day 1-5 years 5-6 mcg/kg/day 6-12 years 4-5 mcg/kg/day Greater than 12 years but growth and puberty incomplete 2-3 mcg/kg/day Growth and puberty complete 1. 6 mcg/kg/day a. The dose should be adjusted based on clinical response and laboratory parameters [see Dosage and Administration (2. 4) and Use in Specific Populations (8. Newborns (0-3 months) at risk for cardiac failure: Children at risk for hyperactivity: Pregnancy Pre-existing Hypothyroidism: New Onset Hypothyroidism: [see Use in Specific Populations (8. TSH Suppression in Well-differentiated Thyroid Cancer Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of levothyroxine sodium tablets may be evidence of inadequate absorption, poor compliance, drug interactions or a combination of these factors. Adults Pediatrics While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. Failure of the serum T4 to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium tablets therapy and/or of the serum TSH to decrease below 20 IU per liter within 4 weeks may indicate the child is not receiving adequate therapy. Assess compliance, dose of medication administered and method of administration prior to increasing the dose of levothyroxine sodium tablets [see Warnings and Precautions (5. 1) and Use in Specific Populations (8. Secondary and Tertiary Hypothyroidism.

Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5), Overdosage (10)]. General: Central nervous system: Musculoskeletal: Cardiovascular: Respiratory: Gastrointestinal: Dermatologic: Endocrine: Reproductive: Seizures have been reported rarely with the institution of levothyroxine therapy. Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, muscle spasm, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities and skin rash. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Adverse Reactions in Children 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. Hypersensitivity Reactions Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
Thyroid hormones, including levothyroxine sodium tablets, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects [see Adverse Reactions (6), Drug Interactions (7. 7) and Overdosage (10)]. WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS See full prescribing information for complete boxed warning Thyroid hormones, including levothyroxine sodium tablets should not be used for the treatment of obesity or for weight loss. Doses beyond the range of daily hormonal requirements may produce serious or even life threatening manifestations of toxicity (6, 10).
CONTRAINDICATIONS
Levothyroxine sodium tablets is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (5. Uncorrected adrenal insufficiency.

Pregnancy may require the use of higher doses of levothyroxine sodium tablets. 1) Experience with levothyroxine use in pregnant women, including data from post-marketing studies, have not reported increased rates of major birth defects or miscarriages [see Data] [see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development. Pregnancy may increase levothyroxine sodium tablets requirements. Serum TSH levels should be monitored and the levothyroxine sodium tablets dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the levothyroxine sodium tablets dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2. Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women. Limited published studies report that levothyroxine is present in human milk. However, there is insufficient information to determine the effects of Levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levothyroxine sodium tablets and any potential adverse effects on the breastfed infant from levothyroxine sodium tablets or from the underlying maternal condition. The initial dose of levothyroxine sodium tablets varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters [see Dosage and Administration (2. In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue levothyroxine sodium tablets administration for a trial period, but only after the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, and use laboratory test results and clinical assessment to guide diagnosis and treatment, if warranted. Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate levothyroxine sodium tablets therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients. Closely monitor infants during the first 2 weeks of levothyroxine sodium tablets therapy for cardiac overload, arrhythmias and aspiration from avid suckling. Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. Closely monitor patients 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. Because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium tablets at less than the full replacement dose [see Warnings and Precautions (5. 1) and Dosage and Administration (2.

See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e. , absorption, synthesis, secretion, catabolism, protein binding and target tissue response) and may alter the therapeutic response to levothyroxine sodium tablets. (7) Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e. , absorption, synthesis, secretion, catabolism, protein binding and target tissue response) and may alter the therapeutic response to levothyroxine sodium tablets (see Tables 2-5 Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium tablets by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Calcium Carbonate Ferrous Sulfate Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric- thyroxine complex. Administer levothyroxine sodium tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and levothyroxine sodium tablets for changes in thyroid function. Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels. Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH and reduce levothyroxine absorption. Monitor patients appropriately. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class Effect Mitotane Tamoxifen These drugs may increase serum thyroxine-binding globulin (TBG) concentration. Androgens / Anabolic Steroids These drugs may decrease serum TBG concentration. Potential impact (below): Administration of these agents with levothyroxine sodium tablets results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. Salicylates (>2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. Other drugs: Carbamazepine Furosemide (>80 mg IV) These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine sodium tablets requirements. Drug or Drug Class Effect Phenobarbital Rifampin Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. Drugs That May Decrease Conversion of T4 to T3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class Effect Beta-adrenergic antagonists (e. , Propranolol >160 mg/day) In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change, TSH levels remain normal and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). Other drugs: Amiodarone Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4 and decreased or normal free-T3) in clinically euthyroid patients. Addition of levothyroxine sodium tablets therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed or discontinued [see Warnings and Precautions (5. Levothyroxine sodium tablets increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the levothyroxine sodium tablets dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. Levothyroxine sodium tablets may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. Concurrent use of tricyclic (e. , amitriptyline) or tetracyclic (e. , maprotiline) antidepressants and levothyroxine sodium tablets may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. Levothyroxine sodium tablets may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium tablets may result in increased levothyroxine sodium tablets requirements. Concurrent use of ketamine and levothyroxine sodium tablets may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. Concurrent use of sympathomimetics and levothyroxine sodium tablets may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients. Consumption of certain foods may affect levothyroxine sodium tablets absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2. Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.

OVERDOSAGE
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6)]. Reduce the levothyroxine sodium tablets dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s medical status. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.
NONCLINICAL TOXICOLOGY
Standard animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine.

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LEVOTHYROXINE SODIUM- levothyroxine sodium_tablet Product manual source documgent