Synthroid

1 INDICATIONS AND USAGE Hypothyroidism SYNTHROID is indicated in adult and pediatric patients, including neonates, as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid -Stimulating Hormone, TSH) Suppression SYNTHROID is indicated in adult and pediatric patients, including neonates, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Limitations of Use SYNTHROID 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 SYNTHROID may induce hyperthyroidism [see Warnings and Precautions ( 5.1 )]. SYNTHROID is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. SYNTHROID is a L-thyroxine (T4) indicated in adult and pediatric patients, including neonates, for: Hypothyroidism: As replacement therapy 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 thyrotropin-dependent well-differentiated thyroid cancer. ( 1 ) Limitations of Use: Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis

2 DOSAGE AND ADMINISTRATION Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast. ( 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 ) Advise patients to stop biotin and biotin-containing supplements at least 2 days before assessing TSH and/or T4 levels. ( 2.2 ) Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, and concomitant medications. Peak therapeutic effect may not be attained for 4-6 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 Important Administration Instructions Administer SYNTHROID as a single daily dose, on an empty stomach, one-half to one hour before breakfast. Administer SYNTHROID at least 4 hours before or after drugs known to interfere with SYNTHROID absorption [see Drug Interactions ( 7.1 ) ] . Evaluate the need for dosage adjustments when regularly administering within one hour of certain foods that may affect SYNTHROID absorption [see Dosage and Administration ( 2.2 and 2.3 ), Drug Interactions ( 7.9 ) , and Clinical Pharmacology ( 12.3 ) ] . Administer SYNTHROID to pediatric patients who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL) of water and immediately administering the suspension by spoon or dropper. Ensure the patient ingests the full amount of the suspension. Do not store the suspension. Do not administer in foods that decrease absorption of SYNTHROID, such as soybean-based infant formula [see Drug Interactions ( 7.9 ) ] . 2.2 Important Considerations for Dosing The dosage of SYNTHROID 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 )] . Dosing must be individualized to account for these factors and dosage adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration ( 2.4 )] . For adult patients with primary hypothyroidism, titrate until the patient is clinically euthyroid and the serum TSH returns to normal [see Dosage and Administration ( 2.3 )] . For secondary or tertiary hypothyroidism, serum TSH is not a reliable measure of SYNTHROID dosage adequacy and should not be used to monitor therapy. Use the serum free-T4 level to titrate SYNTHROID dosing until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range [see Dosage and Administration ( 2.3 )] . Inquire whether patients are taking biotin or biotin-containing supplements. If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7.10 )]. The peak therapeutic effect of a given dose of SYNTHROID may not be attained for 4 to 6 weeks. 2.3 Recommended Dosage and Titration Primary, Secondary, and Tertiary Hypothyroidism in Adults The recommended starting daily dosage of SYNTHROID in adults with primary, secondary, or tertiary hypothyroidism is based on age and comorbid cardiac conditions, as described in Table 1. For patients at risk of atrial fibrillation or patients with underlying cardiac disease, start with a lower dosage and titrate the dosage more slowly to avoid exacerbation of cardiac symptoms. Dosage titration is based on serum TSH or free-T4 [see Dosage and Administration ( 2.2 )] . Table 1. SYNTHROID Dosing Guidelines for Hypothyroidism in Adults* Patient Population Starting Dosage Dosage Titration Based on Serum TSH or Free-T4 Adults diagnosed with hypothyroidism Full replacement dose is 1.6 mcg/kg/day. Some patients require a lower starting dose. Titrate dosage by 12.5 to 25 mcg increments every 4 to 6 weeks, as needed until the patient is euthyroid. Adults at risk for atrial fibrillation or with underlying cardiac disease Lower starting dose (less than 1.6 mcg/kg/day) Titrate dosage every 6 to 8 weeks, as needed until the patient is euthyroid. Geriatric patients Lower starting dose (less than 1.6 mcg/kg/day) * Dosages greater than 200 mcg/day are seldom required. An inadequate response to daily dosages greater than 300 mcg/day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors [see Dosage and Administration ( 2.1 ) and Drug Interactions (7) ] . Primary, Secondary, and Tertiary Hypothyroidism in Pediatric Patients The recommended starting daily dosage of SYNTHROID in pediatric patients with primary, secondary, or tertiary hypothyroidism is based on body weight and changes with age as described in Table 2. Titrate the dosage (every 2 weeks) as needed based on serum TSH or free-T4 until the patient is euthyroid [see Dosage and Administration ( 2.2 )] . Table 2. SYNTHROID Dosing Guidelines for Hypothyroidism in Pediatric Patients Ag e Starting Daily Dos ag e Per Kg Body Weight * 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 * Adjust dosage based on clinical response and laboratory parameters [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.4 ) ] . Pediatric Patients from Birth to 3 Months of Age at Risk for Cardiac Failure Start at a lower starting dosage and increase the dosage 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, start at one-fourth the recommended full replacement dosage, and increase on a weekly basis by one-fourth the full recommended replacement dosage until the full recommended replacement dosage is reached. Hypothyroidism in Pregnant Patients For pregnant patients with pre-existing hypothyroidism, measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy. In pregnant patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. The recommended daily dosage of SYNTHROID in pregnant patients is described in Table 3. Table 3. SYNTHROID Dosing Guidelines for Hypothyroidism in Pregnant Patients Patient Population Starting Dosage Dose Adjustment and Titration Pre-existing primary hypothyroidism with serum TSH above normal trimester-specific range Pre-pregnancy dosage may increase during pregnancy Increase SYNTHROID dosage by 12.5 to 25 mcg per day. Monitor TSH every 4 weeks until a stable dose is reached and serum TSH is within normal trimester-specific range. Reduce SYNTHROID dosage to pre-pregnancy levels immediately after delivery. Monitor serum TSH 4 to 8 weeks postpartum. New onset hypothyroidism (TSH ≥ 10 mIU per liter) 1.6 mcg/kg/day Monitor serum TSH every 4 weeks and adjust SYNTHROID dosage until serum TSH is within normal trimester-specific range. New onset hypothyroidism (TSH < 10 mIU per liter) 1.0 mcg/kg/day TSH Suppression in Well-differentiated Thyroid Cancer in Adult and Pediatric Patients The SYNTHROID dosage is based on the target level of TSH suppression for the stage and clinical status of thyroid cancer. 2.4 Monitoring TSH and/or Thyroxine (T4) Levels Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. Biotin supplementation may interfere with immunoassays for TSH, T4, and T3, resulting in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days before assessing TSH and/or T4 levels [see Drug Interactions ( 7.10 )]. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of SYNTHROID 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 dosage. In patients on a stable and appropriate replacement dosage, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient’s clinical status. Pediatric Patients In patients with 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 pediatric patients 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 dosage 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. 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 SYNTHROID therapy and/or of the serum TSH to decrease below 20 mIU per liter within 4 weeks may indicate the patient is not receiving adequate therapy. Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of SYNTHROID [see Warnings and Precautions ( 5.1 ) and 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 SYNTHROID tablets are available as follows ( Table 4 ): Table 4: SYNTHROID Tablet Strengths and Identifying Features Tablet Strength Tablet Color/Shape Tablet Markings 25 mcg Orange/Round “SYNTHROID” and “25” 50 mcg White/Round “SYNTHROID” and “50” 75 mcg Violet/Round “SYNTHROID” and “75” 88 mcg Olive/Round “SYNTHROID” and “88” 100 mcg Yellow/Round “SYNTHROID” and “100” 112 mcg Rose/Round “SYNTHROID” and “112” 125 mcg Brown/Round “SYNTHROID” and “125” 137 mcg Turquoise/Round “SYNTHROID” and “137” 150 mcg Blue/Round “SYNTHROID” and “150” 175 mcg Lilac/Round “SYNTHROID” and “175” 200 mcg Pink/Round “SYNTHROID” and “200” 300 mcg Green/Round “SYNTHROID” and “300” Tablets: 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 mcg ( 3 )

4 CONTRAINDICATIONS SYNTHROID is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions ( 5.4 ) ] . Uncorrected adrenal insufficiency. ( 4 )

5 WARNINGS AND PRECAUTIONS Serious risks related to overtreatment or undertreatment with SYNTHROID: Titrate the dose of SYNTHROID carefully and monitor response to titration. ( 5.1 ) Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate SYNTHROID at less than the full replacement dose because of the increased risk of cardiac adverse reactions, including atrial fibrillation. ( 2.3 , 5.2 , 8.5 ) Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. ( 5.3 ) Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement glucocorticoids prior to initiation of SYNTHROID treatment. ( 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 Serious Risks Related to Overtreatment or Undertreatment with SYNTHROID SYNTHROID has a narrow therapeutic index. Overtreatment or undertreatment with SYNTHROID may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function, and glucose and lipid metabolism in adult or pediatric patients. In pediatric patients with congenital and acquired hypothyroidism, undertreatment may adversely affect cognitive development and linear growth, and overtreatment is associated with craniosynostosis and acceleration of bone age [see Use in Specific Populations ( 8.4 )] . Titrate the dose of SYNTHROID carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4) ] . Consider the potential for food or drug interactions and adjust the administration or dosage of SYNTHROID as needed [see Dosage and Administration ( 2.1 ), Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ] . 5. 2 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Over-treatment 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 SYNTHROID 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 ) and Use in Specific Populations ( 8.5 ) ] . Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive SYNTHROID therapy. Monitor patients receiving concomitant SYNTHROID and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the SYNTHROID dose or withhold for one week and restart at a lower dose. 5. 3 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. 4 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 SYNTHROID [see Contraindications ( 4 )] . 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 SYNTHROID [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 SYNTHROID that achieves the desired clinical and biochemical response to mitigate this risk.

6 ADVERSE REACTIONS Adverse reactions associated with SYNTHROID therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions ( 5 ) and 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, muscle spasm 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, rash Endocrine: decreased bone mineral density Reproductive: menstrual irregularities, impaired fertility Seizures have been reported rarely with the institution of levothyroxine therapy. 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 who have not undergone complete closure of the fontanelles, and in premature closure of the epiphyses in pediatric patients still experiencing growth 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. Adverse reactions associated with SYNTHROID 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 AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied SYNTHROID (levothyroxine sodium, USP) tablets are supplied as follows ( Table 11 ): Table 11: SYNTHROID Tablet Presentations Strength (mcg) Color/Shape Tablet Markings NDC# for bottles of 90 NDC # for bottles of 1000 NDC # for unit dose cartons of 100 25 Orange/Round “SYNTHROID” and “25” 0074-4341-90 0074-4341-19 -- 50 White/Round “SYNTHROID” and “50” 0074-4552-90 0074-4552-19 0074-4552-11 75 Violet/Round “SYNTHROID” and “75” 0074-5182-90 0074-5182-19 0074-5182-11 88 Olive/Round “SYNTHROID” and “88” 0074-6594-90 0074-6594-19 -- 100 Yellow/Round “SYNTHROID” and “100” 0074-6624-90 0074-6624-19 0074-6624-11 112 Rose/Round “SYNTHROID” and “112” 0074-9296-90 0074-9296-19 -- 125 Brown/Round “SYNTHROID” and “125” 0074-7068-90 0074-7068-19 0074-7068-11 137 Turquoise/Round “SYNTHROID” and “137” 0074-3727-90 0074-3727-19 -- 150 Blue/Round “SYNTHROID” and “150” 0074-7069-90 0074-7069-19 0074-7069-11 175 Lilac/Round “SYNTHROID” and “175” 0074-7070-90 0074-7070-19 -- 200 Pink/Round “SYNTHROID” and “200” 0074-7148-90 0074-7148-19 0074-7148-11 300 Green/Round “SYNTHROID” and “300” 0074-7149-90 0074-7149-19 -- Storage and Handling Store SYNTHROID at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). SYNTHROID tablets should be protected from light and moisture.