ERMEZA

ERMEZA (levothyroxine sodium) oral solution contains synthetic L-3,3', 5,5'-tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is chemically identical to that produced in the human thyroid gland, and is very slightly soluble in water. Levothyroxine (T4) sodium hydrate has an empirical formula of C 15 H 10 I 4 NNaO 4 with x ≈ 5*, molecular weight of 798.86 (anhydrous), and structural formula as shown: ERMEZA oral solution is supplied in the following strength: 150 mcg/5 mL (30 mcg/mL). ERMEZA oral solution contains the following inactive ingredients: edetate disodium, glycerin, and purified water. Levothyroxine Sodium Structural Formula

Hypothyroidism ERMEZA 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 ERMEZA 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: • ERMEZA 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 ERMEZA may induce hyperthyroidism [see Warnings and Precautions (5.1) ]. • ERMEZA is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. ERMEZA is levothyroxine sodium (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: 3. Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients 4. Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis

• 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 levothyroxine absorption. ( 2.1 ) • Administer orally using the appropriate syringe provided in the original carton. The 5 mL syringe should be used for doses up to 5 mL. The 10 mL syringe should be used for doses over 5 mL. ( 2.1 , 2.4 ) • Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, and concomitant medical conditions. 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. ( 2.5 ) 2.1 Important Administration Instructions Administer ERMEZA as a single daily oral dose, on an empty stomach, one-half to one hour before breakfast. Administer ERMEZA at least 4 hours before or after drugs known to interfere with levothyroxine absorption [see Drug Interactions (7.1) ] . Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect levothyroxine absorption [see Dosage and Administration (2.2 and 2.3) , Drug Interactions (7.9) and Clinical Pharmacology (12.3) ] . Convert mcg dosage to mL using the following equation and round up or down to the nearest syringe graduation [see Dosage and Administration (2.4) ]: Administer ERMEZA directly to the mouth using the 5 mL or 10 mL oral syringe provided in the original carton. A household teaspoon or tablespoon is not an adequate measuring device. Instruct patients to read the “Instructions for Use” carefully for complete directions on how to properly dose and administer ERMEZA. mcg dosage to mL conversion 2.2 Important Considerations for Dosing ERMEZA oral solution may have a different concentration from other levothyroxine oral solution products. Use caution and consider the total dosage in terms of mcg and not volume (mL) when converting between ERMEZA and other levothyroxine oral solution products. The dosage of ERMEZA 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 dose adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.5) ] . 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 ERMEZA dosage adequacy and should not be used to monitor therapy. Use the serum free-T4 level to titrate ERMEZA 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) ] . The peak therapeutic effect of a given dose of ERMEZA 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 ERMEZA 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. ERMEZA Dosing Guidelines for Hypothyroidism in Adults 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) ] . 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. Primary, Secondary, and Tertiary Hypothyroidism in Pediatric Patients The recommended starting daily dosage of ERMEZA 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. ERMEZA Dosing Guidelines for Hypothyroidism in Pediatric Patients Age Starting Daily Dosage Per Kg Body Weight Adjust dosage based on clinical response and laboratory parameters [see Dosage and Administration (2.4) and Use in Specific Populations (8.4) ] . 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 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 ERMEZA in pregnant patients is described in Table 3. Table 3. ERMEZA 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 ERMEZA 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 ERMEZA dosage to pre-pregnancy levels immediately after delivery. Monitor serum TSH 4 to 8 weeks postpartum. New onset hypothyroidism (TSH ≥ 10 IU per liter) 1.6 mcg/kg/day Monitor serum TSH every 4 weeks and adjust ERMEZA dosage until serum TSH is within normal trimester specific range. New onset hypothyroidism (TSH < 10 IU per liter) 1.0 mcg/kg/day TSH Suppression in Well-differentiated Thyroid Cancer in Adult and Pediatric Patients The ERMEZA dosage is based on the target level for TSH suppression for the stage and clinical status of thyroid cancer. 2.4 Converting Recommended Microgram Dosage to Milliliters After determination of the recommended ERMEZA dosage in mcg [see Dosage and Administration (2.3) ] , convert the required mcg dosage to mL using the following equation: Once the mcg dose has been converted to mL, it should be rounded up or down to the nearest syringe graduation (0.1 mL for doses up to 5 mL or 0.2 mL for doses up to 10 mL). Example of dosing volumes in mL for the equivalent mcg dosages is shown in Table 4. Table 4: Example Dosing Volumes (mL) for Equivalent Dosages (mcg) Dose (mcg) Dose (mL) using 5 mL syringe Dose (mL) using 10 mL syringe 12.5 0.4 Do not use 25 0.8 50 1.7 75 2.5 88 2.9 100 3.3 112 3.7 125 4.2 137 4.6 150 5.0 175 Do not use 5.8 200 6.6 300 10.0 The 5 mL syringe provided in the original carton should be used for doses up to 5 mL with each graduation mark representing 0.1 mL. The 10 mL syringe provided in the original carton should be used for doses over 5 mL with each graduation mark representing 0.2 mL. mcg dosage to mL conversion 2.5 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 ERMEZA, may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors. The risk of thyroid imbalance can be linked to the switch between levothyroxine-containing products. Assess the adequacy of therapy by assessment of laboratory tests, and clinical evaluation is recommended. 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 dose, 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 ERMEZA 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 ERMEZA [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.

ERMEZA is contraindicated in patients with: • Uncorrected adrenal insufficiency [see Warnings and Precautions (5.4) ] . • Hypersensitivity to glycerin and edetate disodium, inactive ingredients in ERMEZA [see Adverse Reactions (6) and Pediatric Use (8.4) ] . • Uncorrected adrenal insufficiency. ( 4 ) • Hypersensitivity to glycerin and edetate disodium. ( 4 )

Adverse reactions associated with levothyroxine 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, 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 levothyroxine 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See full prescribing information for drugs that affect thyroid hormone pharmacokinetics (e.g., absorption, synthesis, secretion, metabolism, protein binding, and target tissue response) and may alter the therapeutic response to ERMEZA. ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g., absorption, synthesis, secretion, metabolism, protein binding, and target tissue response) and may alter the therapeutic response to ERMEZA (Tables 5 to 8). Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of ERMEZA by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Phosphate Binders (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum) Phosphate binders may bind to levothyroxine. Administer ERMEZA at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and ERMEZA for changes in thyroid function. Bile Acid Sequestrants -Colesevelam -Cholestyramine -Colestipol Ion Exchange Resins -Kayexalate Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer ERMEZA at least 4 hours prior to these drugs or monitor 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 6. 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 ERMEZA 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 increase 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 7. 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 ERMEZA 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 8. 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 above). Other drugs: 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 ERMEZA 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 thyroid therapy is started, changed, or discontinued [see Warnings and Precautions (5.5) ]. 7.3 Oral Anticoagulants ERMEZA 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 ERMEZA dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides ERMEZA 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 ERMEZA 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. ERMEZA may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on ERMEZA may result in increased ERMEZA requirements. 7.6 Ketamine Concurrent use of ketamine and ERMEZA may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and ERMEZA 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 ERMEZA absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1) ] . Soybean products, such as infant formula and soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of ERMEZA 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 T4 and T3 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 concentration. 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.