18598 Rev04_07Prf1

25 FD&C Yellow No. 6 Aluminum Lake 50 None 75 FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake 88 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake 100 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake 112 D&C Red No. 27 Aluminum Lake 125 FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake 137 FD&C Blue No. 1 Aluminum Lake 150 FD&C Blue No. 2 Aluminum Lake 175 FD&C Blue No. 1 Aluminum Lake, D&C Red No. 27 Aluminum Lake 200 FD&C Red No. 40 Aluminum Lake 300 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake CLINICAL PHARMACOLOGY Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitarythyroid 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 (T4) and L-triiodothyronine (T3), by the thyroid gland. Circulating serum T3 and T4 levels exert a feedback effect on both TRH and TSH secretion. When serum T3 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. T3 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 T3, the majority of which (approximately 80%) is derived from T4 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 T4 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 UNITHROID 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 soybean infant formula. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption (see PRECAUTIONS, Drug Interactions 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 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 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 T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3; with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3). T3 and rT3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation. Elimination Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged 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 Biologic t⁄2 Protein Thyroglobulin Potency (days) Binding (%)2 Levothyroxine (T4) 10 20 1 6-71 99.96 Liothyronine (T3) 1 4 ≤2 99.5 1 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism; 2 Includes TBG, TBPA, and TBA 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 Iymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter (see WARNINGS and PRECAUTIONS), and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropindependent well-differentiated thyroid cancer. CONTRAINDICATIONS Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 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). UNITHROID is contraindicated in patients with hypersensitivity to any of the inactive ingredients in UNITHROID tablets. (See DESCRIPTION, Inactive Ingredients). WARNINGS WARNING: Thyroid hormones, including UNITHROID, either alone or with other therapeutic agents, should not be used for the treatment of obesity 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 anore ctic 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, UNITHROID 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 overor undertreatment. 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 increased bone resorption, thereby decreasing bone mineral density, especially in post-menopausal 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 diseaseExercise 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 diseaseExercise 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 UNITHROID: 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 UNITHROID. 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 UNITHROID 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 UNITHROID 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 UNITHROID in the morning on an empty stomach, at least one-half hour to one hour before eating any food. 6. It may take several weeks before you notice an improvement in your symptoms. 7. 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. 8. Notify your physician if you become pregnant while taking UNITHROID. It is likely that your dose of UNITHROID will need to be increased while you are pregnant. 9. Notify your physician or dentist that you are taking UNITHROID prior to any surgery. 10. Partial hair loss may occur rarely during the first few months of UNITHROID therapy, but this is usually temporary. 11. UNITHROID should not be used as a primary or adjunctive therapy in a weight control program. 12. Keep UNITHROID out of the reach of children. Store UNITHROID away from heat, moisture, and light. 13. Agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine sodium tablets. Therefore, levothyroxine sodium tablets should not be administered within 4 hrs of these agents. Laboratory Tests General The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation assay sensitivity ≤ 0.1 mlU/L or third generation assay sensitivity ≤ 0.01 mlU/L) and measurement of free-T4. 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 UNITHROID 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 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 UNITHROID. (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 totalor free-T4. During the first three years of life, the serum totalor 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 UNITHROID 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 UNlTHROID. The recommended frequency of monitoring of TSH and total or free T4 in children is as follows: at 2 and 4 weeks after the initiation of treatment; every 1-2 months during the first year of life; every 2-3 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 T4 levels, and a physical examination, if indicated, be performed 2 weeks after any change in UNITHROID dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation should be performed at regular intervals (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION). Secondary (pituitary) and tertiary (hypothalamic) hypothyroidism Adequacy of therapy should be assessed by measuring serum free-T4 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 UNITHROID. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and action 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.