Levoxyl

1 INDICATIONS AND USAGE LEVOXYL is L-thyroxine (T4) indicated in pediatric and adult patients for: Hypothyroidism: As replacement in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. ( 1 ) Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) suppression: As an adjunct to surgery and radioiodine therapy in the management of well-differentiated thyroid cancer. ( 1 ) Limitations of Use : - Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients. ( 1 ) - Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. ( 1 ) Hypothyroidism LEVOXYL is indicated in pediatric and adult patients as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression LEVOXYL is indicated in pediatric and adult patients as an adjunct to surgery and radioiodine therapy in the management of well-differentiated thyroid cancer . Limitations of Use : LEVOXYL is not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and overtreatment with LEVOXYL may induce hyperthyroidism [see Warnings and Precautions (5.4) ] . LEVOXYL is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

2 DOSAGE AND ADMINISTRATION Administer once daily, on an empty stomach, one-half to one hour before breakfast with a full glass of water. ( 2.1 ) Administer at least 4 hours before or after drugs that are known to interfere with absorption. ( 2.1 ) Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect absorption. ( 2.1 ) Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food, and the specific nature of the condition being treated. Peak therapeutic effect may not be attained for 4 to 6 weeks. ( 2.2 ) See full prescribing information for dosing in specific patient populations. ( 2.3 ) Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status. ( 2.4 ) 2.1 General Administration Information Administer LEVOXYL tablets orally as a single daily dose, on an empty stomach, one-half to one hour before breakfast with a full glass of water to avoid choking or gagging [see Adverse Reactions (6) ]. Administer LEVOXYL at least 4 hours before or after drugs that are known to interfere with LEVOXYL absorption [see Drug Interactions (7.1) ] . Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect LEVOXYL absorption [see Drug Interactions (7.9) , Clinical Pharmacology (12.3) ]. Administer LEVOXYL to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 mL to 10 mL or 1 teaspoon to 2 teaspoons) of water and immediately administering the suspension by spoon or dropper. Do not store the suspension. Do not administer in foods that decrease absorption of LEVOXYL, such as soybean-based infant formula [see Drug Interactions (7.9) ]. 2.2 General Principles of Dosing The dose of LEVOXYL 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) , Drug Interactions (7) ] . Dosing must be individualized to account for these factors and dose adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.4) ] . The peak therapeutic effect of a given dose of LEVOXYL may not be attained for 4 to 6 weeks. 2.3 Dosing in Specific Populations Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty Are Complete Start LEVOXYL 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 LEVOXYL is approximately 1.6 mcg per kg per day (for example: 100 mcg per day to 125 mcg per day for a 70 kg adult). Adjust the dose by 12.5 mcg 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 mcg 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 LEVOXYL may be less than 1 mcg per kg per day in elderly patients. In patients with severe longstanding hypothyroidism, start with a dose of 12.5 mcg to 25 mcg per day. Adjust the dose in 12.5 mcg 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 LEVOXYL 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 LEVOXYL 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 LEVOXYL 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 LEVOXYL in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start LEVOXYL at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0 to 3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response [see Dosage and Administration (2.4) ] . Table 1: LEVOXYL Dosing Guidelines for Pediatric Hypothyroidism Age Daily Dose Per Kg Body Weight - The dose should be adjusted based on clinical response and laboratory parameters [see Warnings and Precautions (5.4) , Drug Interactions (7.10) , Use in Specific Populations (8.4) ] . 0 to 3 months 10 mcg/kg daily to 15 mcg/kg daily 3 to 6 months 8 mcg/kg daily to 10 mcg/kg daily 6 to 12 months 6 mcg/kg daily to 8 mcg/kg daily 1 to 5 years 5 mcg/kg daily to 6 mcg/kg daily 6 to 12 years 4 mcg/kg daily to 5 mcg/kg daily Greater than 12 years but growth and puberty incomplete 2 mcg/kg daily to 3 mcg/kg daily Growth and puberty complete 1.6 mcg/kg daily Newborns (0 to 3 months) at Risk for Cardiac Failure : Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response. Pediatric Patients at Risk for Hyperactivity: To minimize the risk of hyperactivity in pediatric patients, start at one-fourth the recommended full replacement dose, and increase on a weekly basis by one-fourth the full recommended replacement dose until the full recommended replacement dose is reached. Pregnancy Pre-existing Hypothyroidism: LEVOXYL dose requirements may increase during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. For patients with serum TSH above the normal trimester-specific range, increase the dose of LEVOXYL by 12.5 mcg daily to 25 mcg daily and measure TSH every 4 weeks until a stable LEVOXYL dose is reached and serum TSH is within the normal trimester-specific range. Reduce LEVOXYL dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure LEVOXYL dose is appropriate. New Onset Hypothyroidism: Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs and symptoms of hypothyroidism, start LEVOXYL at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH less than 10 mIU per liter) start LEVOXYL at 1 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust LEVOXYL dosage until a serum TSH is within the normal trimester-specific range [see Use in Specific Populations (8.1) ] . TSH Suppression in Well-Differentiated Thyroid Cancer The dose of LEVOXYL should target TSH levels within the desired therapeutic range. This may require a LEVOXYL dose of greater than 2 mcg per kg per day, depending on the target level for TSH suppression. 2.4 Monitoring TSH and/or Thyroxine (T4) Levels 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 LEVOXYL may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors. Adults In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8 weeks after any change in dose. In patients on a stable and appropriate replacement dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient's clinical status. Pediatrics In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dose stabilization until growth is completed. Poor compliance or abnormal values may necessitate more frequent monitoring. Perform routine clinical examination, including assessment of development, mental and physical growth, and bone maturation, at regular intervals. 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 LEVOXYL therapy and/or of the serum TSH to decrease below 20 mIU 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 LEVOXYL [see Warnings and Precautions (5.4) , Use in Specific Populations (8.4) ] . Secondary and Tertiary Hypothyroidism Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.

3 DOSAGE FORMS AND STRENGTHS LEVOXYL tablets are oval, color-coded and, potency marked available as follows: Strength (mcg) Color Tablet Markings 25 Orange 25 50 White 50 75 Purple 75 88 Olive 88 100 Yellow 100 112 Rose 112 125 Light Brown 125 137 Dark Blue 137 150 Blue 150 175 Turquoise 175 200 Pink 200 Tablets: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg ( 3 )

4 CONTRAINDICATIONS Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (5.3) ] . Uncorrected adrenal insufficiency. ( 4 )

5 WARNINGS AND PRECAUTIONS Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate LEVOXYL at less than the full replacement dose because of the increased risk of cardiac adverse reactions, including atrial fibrillation. ( 2.3 , 5.1 , 8.5 ) Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. ( 5.2 ) Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement glucocorticoids prior to initiation of LEVOXYL treatment. ( 5.3 ) Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper dose titration and careful monitoring is critical to prevent the persistence of hypothyroidism or the development of hyperthyroidism. ( 5.4 ) Worsening of diabetic control: Therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing thyroid hormone therapy. ( 5.5 ) Decreased bone mineral density associated with thyroid hormone over-replacement: Over-replacement can increase bone resorption and decrease bone mineral density. Give the lowest effective dose. ( 5.6 ) 5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Overtreatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate LEVOXYL therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Dosage and Administration (2.3) , Use in Specific Populations (8.5) ] . Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive LEVOXYL therapy. Monitor patients receiving concomitant LEVOXYL and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiovascular symptoms develop or worsen, reduce or withhold the LEVOXYL dose for one week and restart at a lower dose. 5.2 Myxedema Coma Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma. 5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with LEVOXYL [see Contraindications (4) ] . 5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism LEVOXYL has a narrow therapeutic index. Over- or undertreatment with LEVOXYL may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Titrate the dose of LEVOXYL carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4) ] . Monitor for the presence of drug or food interactions when using LEVOXYL and adjust the dose as necessary [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] . 5.5 Worsening of Diabetic Control Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing LEVOXYL [see Drug Interactions (7.2) ] . 5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. 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. Administer the minimum dose of LEVOXYL that achieves the desired clinical and biochemical response to mitigate against this risk.

6 ADVERSE REACTIONS Common adverse reactions with LEVOXYL therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5.4) , Overdosage (10) ] . They include the following: General : fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating Central nervous system : headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia Musculoskeletal : tremors, muscle weakness and cramps Cardiovascular : palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest Respiratory : dyspnea Gastrointestinal : diarrhea, vomiting, abdominal cramps, elevations in liver function tests Dermatologic : hair loss, flushing Endocrine : decreased bone mineral density Reproductive : menstrual irregularities, impaired fertility Seizures have been reported rarely with levothyroxine therapy. Common adverse reactions for LEVOXYL 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 Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Adverse Reactions in Pediatric Patients Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphysis in pediatric patients 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. Choking and Gagging on LEVOXYL Tablets There have been reports of choking, gagging, tablet stuck in throat, and dysphagia with LEVOXYL tablets, predominately when LEVOXYL tablets were not taken with water [see Dosage and Administration (2.1) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING LEVOXYL (levothyroxine sodium) tablets are oval, color-coded and, potency marked available as follows: Strength (mcg) Color Tablet Markings NDC - bottles of 100 NDC - bottles of 1000 25 Orange 25 60793-850-01 60793-850-10 50 White 50 60793-851-01 60793-851-10 75 Purple 75 60793-852-01 60793-852-10 88 Olive 88 60793-853-01 60793-853-10 100 Yellow 100 60793-854-01 60793-854-10 112 Rose 112 60793-855-01 60793-855-10 125 Light Brown 125 60793-856-01 60793-856-10 137 Dark Blue 137 60793-857-01 60793-857-10 150 Blue 150 60793-858-01 60793-858-10 175 Turquoise 175 60793-859-01 60793-859-10 200 Pink 200 60793-860-01 60793-860-10 STORAGE CONDITIONS Store between 68°F–77°F (20°C–25°C) with excursions permitted between 59°F–86°F (15°C–30°C). Store LEVOXYL away from heat, moisture, and light.