EUTHYROX

EUTHYROX contains the active ingredient, levothyroxine, a synthetic crystalline levothyroxine (T 4 ) in sodium salt form. It is chemically designated as L-3,3',5,5'-tetraiodothyronine monosodium hydrate. Synthetic T 4 is identical in chemical structure to the T 4 produced in the human thyroid gland. Levothyroxine sodium has the molecular formula C 15 H 10 I 4 NNaO 4 ∙ x H 2 O, molecular weight of 798.85 (anhydrous), and structural formula as shown: EUTHYROX tablets for oral administration are supplied in the following strengths: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, and 200 mcg. Inactive ingredients citric acid anhydrous, corn starch, gelatin, magnesium stearate, mannitol, sodium croscarmellose. chemical

EUTHYROX 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 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. ( 1 ) - Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. ( 1 ) Hypothyroidism EUTHYROX 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 EUTHYROX is indicated in pediatric and adult patients as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer . Limitations of Use: EUTHYROX 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 EUTHYROX may induce hyperthyroidism [see Warnings and Precautions (5.4) ]. EUTHYROX is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

Administer once daily, 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 ) 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 EUTHYROX tablets orally as a single daily dose, on an empty stomach, one-half to one hour before breakfast. Administer EUTHYROX at least 4 hours before or after drugs known to interfere with EUTHYROX absorption [see Drug Interactions (7.1) ]. Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect EUTHYROX absorption [see Drug Interactions (7.9) , Clinical Pharmacology (12.3) ]. Administer EUTHYROX 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 EUTHYROX, such as soybean-based infant formula [see Drug Interactions (7.9) ]. 2.2 General Principles of Dosing The dose of EUTHYROX 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 EUTHYROX 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 EUTHYROX 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 EUTHYROX 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 per day 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 EUTHYROX 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 per day 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 EUTHYROX 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 EUTHYROX dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 (L-thyroxine) level to monitor adequacy of therapy in this patient population. Titrate EUTHYROX 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 EUTHYROX in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start EUTHYROX 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. EUTHROX 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 Dosage and Administration (2.4) , 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: EUTHYROX dose requirements may increase during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at a 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 EUTHYROX by 12.5 mcg daily to 25 mcg daily and measure TSH every 4 weeks until a stable EUTHYROX dose is reached and serum TSH is within the normal trimester-specific range. Reduce EUTHYROX dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure EUTHYROX 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 EUTHYROX 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 EUTHYROX at 1 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust EUTHYROX 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 EUTHYROX should target TSH levels within the desired therapeutic range. This may require a EUTHYROX 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 (T 4 ) 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 EUTHYROX 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 EUTHYROX 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 EUTHYROX [see Warnings and Precautions (5.4) 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.

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

Adverse reactions associated with EUTHYROX therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5) , 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, muscular 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 and 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 levothyroxine therapy. Adverse reactions associated with EUTHYROX 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 Provell Pharmaceuticals, LLC at 1-888-899-7041 or FDA at1-800-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 epiphyses 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.

See full prescribing information for drugs that 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 EUTHYROX. ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to EUTHYROX (see Tables 2 – 5). Table 2: Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of EUTHYROX 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 EUTHYROX at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and EUTHYROX for changes in thyroid function. Bile Acid Sequestrants -Colesevelam -Cholestyramine -Colestipol Ion Exchange Resins -Kayexalate -Sevelamer Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer EUTHYROX at least 4 hours prior to these drugs or monitor thyrotropin (TSH) levels. Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone 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. Table 3: Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free-Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class Effect Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen These drugs may increase serum thyroxine-binding globulin (TBG) concentration. Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid These drugs may decrease serum TBG concentration. Potential impact (below) : Administration of these agents with EUTHYROX 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) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates 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 increased 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. Table 4: 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 EUTHYROX 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. Table 5: 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.g., 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 the hypothyroid patient is converted to the euthyroid state. Glucocorticoids (e.g., Dexamethasone ≥ 4 mg/day) 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 Table 3 above). Other: Amiodarone Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decrease or normal free-T3) in clinically euthyroid patients. 7.2 Antidiabetic Therapy Addition of EUTHYROX 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 EUTHYROX is started, changed, or discontinued [see Warnings and Precautions (5.5) ]. 7.3 Oral Anticoagulants EUTHYROX 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 EUTHYROX dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides EUTHYROX 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. 7.5 Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and EUTHYROX 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. EUTHYROX may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on EUTHYROX may result in increased EUTHYROX requirements. 7.6 Ketamine Concurrent use of ketamine and EUTHYROX may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and EUTHYROX 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. 7.8 Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients. 7.9 Drug-Food Interactions Consumption of certain foods may affect EUTHYROX absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1) ]. Soybean flour (infant formula), cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of EUTHYROX from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. 7.10 Drug–Laboratory Test Interactions Consider changes in TBG concentration when interpreting T 4 and T 3 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 concentrations. 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.

Store between 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light and moisture, avoid heat. Do not separate the individual cavities containing the tablet from the intact blister and do not remove the individual tablets from blister packaging until ready to use.