Levoxyl (levothyroxine sodium) Tablet

  Levoxyl (levothyroxine sodium)  Tablet [King Pharmaceuticals, Inc.] DESCRIPTION –LEVOXYL® (levothyroxine sodium tablets, USP) contain synthetic crystalline L-3,3’,5,5’- tetraiodothyronine sodium salt [levothyroxine (T ) sodium]. Synthetic T is identical to that 4 4 produced in the human thyroid gland. Levothyroxine (T ) sodium has an empirical formula of 4 C H I N NaO • H O, molecular weight of 798.86 g/mol (anhydrous), and structural formula 15 10 4 4 2 as shown: Inactive Ingredients Microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The following are the coloring additives per tablet strength: Strength (mcg) Color additive(s) 25 FD&C Yellow No. 6 Aluminum Lake FD&C Blue No. 1 Aluminum Lake, D&C Red No. 30 Aluminum Lake FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake FD&C Blue No. 1 Aluminum Lake FD&C Blue No. 1 Aluminum Lake, D&C Red No. 30 Aluminum Lake FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake 200 D&C Red No. 30 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake 75 88 1 100 FD&C Yellow No. 6 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake 112 FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, D&C Red No. 30 Aluminum Lake 25 137 150 175 50 None 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 thyroid-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 4 L-triiodothyronine (T ), by the thyroid gland. Circulating serum T3 3 and T4 levels exert a feedback effect on both TRH and TSH secretion. When serum T 3 and T4 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 3 and 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. 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 physiologic actions of thyroid hormones are produced predominately by T , the majority of 3 which (approximately 80%) is derived from T 4 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 INDICATIONS AND USAGE , PRECAUTIONS , DOSAGE AND ADMINISTRATION ). Pharmacokinetics Absorption — Absorption of orally administered T 4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of LEVOXYL® tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 98%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybean infant formula. Dietary fiber decreases bioavailability of T . Absorption may also decrease with 4 age. In addition, many drugs and foods affect T 4 absorption (see PRECAUTIONS , DrugInteractions and Drug-Food Interactions ). 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 T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T compared to T . Protein-bound thyroid hormones exist in reverse 4 3 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 PRECAUTIONS , Drug Interactions and Drug-Laboratory Test Interactions). Thyroid hormones do not readily cross the placental barrier (see PRECAUTIONS , Pregnancy). Metabolism — T4 is slowly eliminated (see TABLE 1). The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately eighty-percent of circulating T3 is derived from peripheral T by monodeiodination. The liver is the major site of degradation for 4 both T and T , with T deiodination also occurring at a number of additional sites, including4 3 4 the kidney and other tissues. Approximately 80% of the daily dose of T 4 is deiodinated to yield equal amounts of T and reverse T (rT ). T and rT are further deiodinated to 3 3 3 3 3 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 and is eliminated in the feces. Approximately 20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age. Table 1: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency 1/2 Protein Binding (%) Levothyroxine (T ) Liothyronine (T ) 10—20 1 1 4 6—7 ≤ 2 99.96 99.5 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism; Includes TBG, TBPA, and TBA t (days) 2 4 3 1 1 2 INDICATIONS AND USAGE Levothyroxine sodium is used for the following indications: Hypothyroidism — As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter. Pituitary TSH Suppression — In the treatment or prevention of various types of euthyroid goiters (see WARNINGS and PRECAUTIONS ), including thyroid nodules (see WARNINGS and PRECAUTIONS ), subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), multinodular goiter (see WARNINGS and PRECAUTIONS ) and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. CONTRAINDICATIONS Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T 3 and T 4 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 PRECAUTIONS ). LEVOXYL ® is contraindicated in patients with hypersensitivity to any of the inactive ingredients in LEVOXYL® tablets (see DESCRIPTION , Inactive Ingredients ). WARNINGS WARNING: Thyroid hormones, including LEVOXYL , 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. ® 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 CONTRAINDICATIONS ). If the serum TSH level is not suppressed, LEVOXYL® 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. PRECAUTIONS 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 Drug Interactions ). Effects on bone mineral density — In women, long-term levothyroxine sodium therapy has been associated with decreased bone mineral density, especially in postmenopausal women on greater than replacement doses or in women who are receiving suppressive doses of levothyroxine sodium. 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 WARNINGS ; PRECAUTIONS , Geriatric Use ; and DOSAGE AND ADMINISTRATION ). 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 PRECAUTIONS , Autoimmune polyglandular syndrome) for adrenal insufficiency. 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 PRECAUTIONS , Drug Interactions ). 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 ®LEVOXYL : 1. Notify your physician if you are allergic to any foods or medicines, are pregnant or intend to become pregnant, are breast-feeding or are taking any other medications, including prescription and over-the-counter preparations. 2. Notify your physician of any other medical conditions you may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems. Your dose of medications used to control these other conditions may need to be adjusted while you are taking LEVOXYL®. If you have diabetes, monitor your blood and/or urinary glucose levels as directed by your physician and immediately report any changes to your physician. If you are taking anticoagulants (blood thinners), your clotting status should be checked frequently. 3. Use LEVOXYL® only as prescribed by your physician. Do not discontinue or change the amount you take or how often you take it, unless directed to do so by your physician. 4. The levothyroxine in LEVOXYL® is intended to replace a hormone that is normally produced by your thyroid gland. Generally, replacement therapy is to be taken for life, except in cases of transient hypothyroidism, which is usually associated with an inflammation of the thyroid gland (thyroiditis). 5. Take LEVOXYL® in the morning on an empty stomach, at least one-half hour before eating any food. 6. LEVOXYL® may rapidly swell and disintegrate resulting in choking, gagging, the tablet getting stuck in your throat or difficulty swallowing. It is very important that you take the tablet with a full glass of water. Most of these problems disappeared when Levoxyl ® tablets were taken with water. 7. It may take several weeks before you notice an improvement in your symptoms. 8. Notify your physician if you experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event. 9. Notify your physician if you become pregnant while taking LEVOXYL ®. It is likely that your dose of LEVOXYL® will need to be increased while you are pregnant. 10. Notify your physician or dentist that you are taking LEVOXYL® prior to any surgery. 11. Partial hair loss may occur rarely during the first few months of LEVOXYL® therapy, but this is usually temporary. 12. LEVOXYL® should not be used as a primary or adjunctive therapy in a weight control program. 13. Keep LEVOXYL® out of the reach of children. Store LEVOXYL® away from heat, moisture, and light. 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 . 4 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 PRECAUTIONS , Drug Interactions and Drug-Laboratory Test Interactions). Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of LEVOXYL ® may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T4 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—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— 12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6—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 LEVOXYL ® (see WARNINGS , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ). 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 .4 During the first three years of life, the serum total- or free- T4 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 in utero hypothyroidism. Failure of the serum T4 to increase into the upper half of the normal range within 2 weeks of initiation of LEVOXYL® 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