Liomny

1 INDICATIONS AND USAGE LIOMNY is an L-triiodothyronine (T3) indicated for: Hypothyroidism: As replacement in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism ( 1.1 ) Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct to surgery and radioiodine therapy in the management of well-differentiated thyroid cancer ( 1.2 ) Thyroid Suppression Test: As a diagnostic agent in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy ( 1.3 ) 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 ) 1.1 Hypothyroidism LIOMNY is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. 1.2 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression LIOMNY is indicated as an adjunct to surgery and radioiodine therapy in the management of well-differentiated thyroid cancer. 1.3 Thyroid Suppression Test LIOMNY is indicated as a diagnostic agent in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy. Limitations of Use LIOMNY 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 LIOMNY may induce hyperthyroidism [see Warnings and Precautions (5.4) ]. LIOMNY is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

2 DOSAGE AND ADMINISTRATION Administer LIOMNY orally once daily and individual dosage according to patient response and laboratory findings ( 2.1 ) See full prescribing information for recommended dosage for hypothyroidism ( 2.2 ) TSH suppression in well-differentiated thyroid cancer ( 2.3 ) and for thyroid suppression test ( 2.4 ) When switching a patient to LIOMNY discontinue levothyroxine therapy and initiate LIOMNY at a low dosage. Gradually increase the dose according to the patient's response ( 2.5 ) Adequacy of therapy determined with periodic monitoring of TSH and T3 levels as well as clinical status ( 2.6 ) 2.1 General Principles of Dosing The dose of LIOMNY for hypothyroidism or pituitary Thyroid-Stimulating Hormone (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 (2.2 , 2.3 , 2.4 ), 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 (2.4) ]. Administer LIOMNY orally once daily. 2.2 Recommended Dosage for Hypothyroidism Adults The recommended starting dosage is 25 mcg orally once daily. Increase the dose by 25 mcg daily every 1 or 2 weeks, if needed. The usual maintenance dose is 25 mcg to 75 mcg once daily. For elderly patients or patients with underlying cardiac disease, start with LIOMNY 5 mcg once daily and increase by 5 mcg increments at the recommended intervals. Serum TSH is not a reliable measure of LIOMNY dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum T3 level to monitor adequacy of therapy in this patient population. Pediatric Patients The recommended starting dosage is 5 mcg once daily, with a 5 mcg increase every 3 to 4 days until the desired response is achieved. Infants a few months old may require 20 mcg once daily for maintenance. At 1 year of age, 50 mcg once daily may be required. Above 3 years of age, the full adult dosage may be necessary [see Use in Specific Populations (8.4) ]. Newborns (0 to 3 months) at Risk for Cardiac Failure: Consider a lower starting dose in infants at risk for cardiac failure. Increase the dose 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: Thyroid hormone 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 thyroid hormone and measure TSH every 4 weeks until a stable dose is reached and serum TSH is within the normal trimester-specific range. Reduce thyroid hormone dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure thyroid hormone dose is appropriate. 2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer The dose of LIOMNY should target TSH levels within the desired therapeutic range. This may require higher doses, depending on the target level for TSH suppression. 2.4 Recommended Dosage for Thyroid Suppression Test The recommended dose is 75 mcg to 100 mcg daily for 7 days, with radioactive iodine uptake being determined before and after the 7 day administration of LIOMNY. If thyroid function is normal, the radioiodine uptake will drop significantly after treatment. A 50% or greater suppression of uptake indicates a normal thyroid-pituitary axis. 2.5 Switching from Levothyroxine to LIOMNY LIOMNY has a rapid onset of action and residual effects of the other thyroid preparation may persist for the first several weeks after initiating LIOMNY therapy. When switching a patient to LIOMNY, discontinue levothyroxine therapy and initiate LIOMNY at a low dosage. Gradually increase the LIOMNY dose according to the patient's response. 2.6 Monitoring TSH and Triiodothyronine (T3) 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 LIOMNY 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 periodically after initiation of the therapy or any change in dose. To check the immediate response to therapy before the TSH has had a chance to respond or if your patient's status needs to be assessed prior to that point, measurement of total T3 would be most appropriate. 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 pediatric patients with hypothyroidism, assess the adequacy of replacement therapy by measuring serum TSH and T3 levels. For pediatric patients three years of age and older, the recommended monitoring is every 3 to 12 months thereafter, following dose stabilization until growth and puberty are 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 TSH to decrease below 20 IU per liter after initiation of LIOMNY therapy 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 LIOMNY [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)] . Secondary and Tertiary Hypothyroidism Monitor serum T3 levels and maintain in the normal range.

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

5 WARNINGS AND PRECAUTIONS Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate LIOMNY 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 LIOMNY 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 thyroid hormone 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 LIOMNY 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 LIOMNY therapy. Monitor patients receiving concomitant LIOMNY and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiovascular symptoms develop or worsen, reduce or withhold the LIOMNY 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 thyroid hormone 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 LIOMNY [see Contraindications (4) ]. 5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism LIOMNY has a narrow therapeutic index. Over- or undertreatment with LIOMNY 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 LIOMNY 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 LIOMNY and adjust the dose as necessary [see Drug Interactions (7) and Clinical Pharmacology (12.3) ]. 5.5 Worsening of Diabetic Control Addition of thyroid hormone 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 LIOMNY [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 thyroid hormone 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 LIOMNY that achieves the desired clinical and biochemical response to mitigate against this risk.

7 DRUG INTERACTIONS 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 LIOMNY 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 LIOMNY (see Tables 1 - 4). Table 1: Drugs That May Decrease T3 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of LIOMNY by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Bile Acid Sequestrants -Colesevelam -Cholestyramine -Colestipol Ion Exchange Resins -Kayexalate -Sevelamer Bile acid sequestrants and ion exchange resins are known to decrease thyroid hormones absorption. Administer LIOMNY at least 4 hours prior to these drugs or monitor thyrotropin-stimulating hormone (TSH) levels. Table 2: Drugs That May Alter 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. 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 thyroid hormones, and total and FT4 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 3: Drugs That May Alter Hepatic Metabolism of Thyroid hormones Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of thyroid hormones, resulting in increased liothyronine sodium 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 thyroid hormones. Table 4: 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 a 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 decreased or normal free-T3) in clinically euthyroid patients. 7.2 Antidiabetic Therapy Addition of LIOMNY 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 LIOMNY is started, changed, or discontinued [see Warnings and Precautions (5.5) ]. 7.3 Oral Anticoagulants LIOMNY 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 LIOMNY dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides LIOMNY may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may be decreased 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 LIOMNY 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. LIOMNY may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on LIOMNY may result in increased LIOMNY requirements. 7.6 Ketamine Concurrent use of ketamine and LIOMNY may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and LIOMNY 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-Laboratory Test Interactions Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone 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.

6 ADVERSE REACTIONS Adverse reactions associated with LIOMNY therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5.4) 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 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 Adverse Reactions in Pediatric Patients Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving thyroid replacement 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. To report SUSPECTED ADVERSE REACTIONS , contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions for LIOMNY are primarily those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary Experience with liothyronine use in pregnant women, including data from post-marketing studies, have not reported increased rates of major birth defects or miscarriages (see Data ). There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and LIOMNY dosage adjusted during pregnancy (see Clinical Considerations ). There are no animal studies conducted with liothyronine during pregnancy. LIOMNY should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development. Dose adjustments during pregnancy and the postpartum period Pregnancy may increase LIOMNY requirements. Serum TSH levels should be monitored and the LIOMNY dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the LIOMNY dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3) ] . Data Human Data Liothyronine is approved for use as a replacement therapy for hypothyroidism. Data from post-marketing studies have not reported increased rates of fetal malformations, miscarriages, or other adverse maternal or fetal outcomes associated with liothyronine use in pregnant women.