Levothyroxine Sodium

1 INDICATIONS AND USAGE Levothyroxine Sodium Injection is indicated for the treatment of myxedema coma. Levothyroxine Sodium Injection is L-thyroxine (T4) indicated in adult patients for the treatment of myxedema coma. ( 1 ) Limitations of Use: Not recommended as a substitute for oral levothyroxine sodium because the relative bioavailability of Levothyroxine Sodium Injection to oral levothyroxine sodium has not been established and there is a risk of inaccurate dose conversion. ( 1 ) Limitations of Use: Not recommended as a substitute for oral levothyroxine sodium because the relative bioavailability of Levothyroxine Sodium Injection to oral levothyroxine sodium has not been established and there is a risk of inaccurate dose conversion.

2 DOSAGE AND ADMINISTRATION • Consider the age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms when determining dosages of Levothyroxine Sodium Injection. ( 2.1 ) • Start with lower doses in elderly patients and in patients with underlying cardiovascular disease. ( 2.1 ) • The recommended loading dose is 300 mcg to 500 mcg administered intravenously. ( 2.1 ) • The recommended maintenance dose is 50 mcg to 100 mcg administered intravenously daily until the patient can tolerate oral therapy. ( 2.1 ) • Administer Levothyroxine Sodium Injection intravenously at a rate not to exceed 100 mcg per minute. ( 2.2 ) • Do not add Levothyroxine Sodium Injection to intravenous fluids. ( 2.2 ) 2.1 Dosage • Consider the age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms when determining the starting and maintenance dosages of Levothyroxine Sodium Injection. • Start with lower doses in elderly patients and in patients with underlying cardiovascular disease [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.5 )]. • The recommended loading dose of Levothyroxine Sodium Injection is 300 mcg to 500 mcg administered intravenously. • The recommended maintenance dose of Levothyroxine Sodium Injection is 50 mcg to 100 mcg administered intravenously daily until the patient can tolerate oral therapy. 2.2 Administration Instructions • Administer Levothyroxine Sodium Injection as an intravenous injection at a rate not to exceed 100 mcg per minute. • Do not add Levothyroxine Sodium Injection to intravenous fluids. • Inspect Levothyroxine Sodium Injection visually prior to injection. It should appear clear and colorless, solution free of visible particulates. Do not use if particulate matter or coloration is seen. • Discard any unused portion.

5 WARNINGS AND PRECAUTIONS • Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease: Overtreatment may cause arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death, particularly in patients with cardiovascular disease and in elderly patients. Start with lower doses in elderly patients and in patients with underlying cardiovascular disease and monitor patients after administration ( 5.1 ). • Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency: 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 ( 5.2 ). • Worsening of Diabetic Control: May worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control ( 5.3 ). 5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Overtreatment with Levothyroxine Sodium Injection may cause arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death, particularly in patients with cardiovascular disease and in elderly patients. Start with lower doses in elderly patients and in patients with underlying cardiovascular disease and monitor patients after administration of Levothyroxine Sodium Injection for cardiac adverse reactions. 5.2 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency Chronic autoimmune thyroiditis, which can lead to myxedema coma, may occur in association with other autoimmune disorders such as 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 [see Contraindications ( 4 )]. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with Levothyroxine Sodium Injection. 5.3 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 [see Drug Interactions ( 7.2 )].

4 CONTRAINDICATIONS Uncorrected adrenal insufficiency [see Warnings and Precautions ( 5.2 )] Uncorrected adrenal insufficiency. ( 4 )

7 DRUG INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., synthesis, secretion, catabolism, protein binding, and target tissue response) that may alter the therapeutic response to Levothyroxine Sodium Injection. ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium Injection (see Tables 1 - 3 ). Table 1: Drugs That May Alter T 4 and Triiodothyronine (T 3 ) Serum Transport Without Effecting Free Thyroxine (FT 4 ) 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 levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations. Salicylates (> 2 g/day) Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T 4 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 2: Drugs That May Alter Hepatic Metabolism of T 4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine 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 3: Drugs That May Decrease Conversion of T 4 to T 3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3 , leading to decreased T 3 levels. However, serum T 4 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), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that 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 T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in s…

8.1 Pregnancy Risk Summary There is no available data with use of Levothyroxine Sodium Injection in pregnant women. The clinical data in pregnant women treated with oral levothyroxine to maintain a euthyroid state have not reported increased rates of major birth defects, miscarriages, or adverse maternal or fetal outcomes (see Data ). There are risks to the mother and fetus associated with myxedema coma in pregnancy (see Clinical Considerations ) . Animal reproduction studies have not been conducted with levothyroxine sodium. 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 Myxedema coma is a medical emergency which can be fatal, if left untreated. Delaying treatment in pregnant women with myxedema coma increases the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of Levothyroxine Sodium Injection on the fetus. Data Human Data There is no available data with use of Levothyroxine Sodium Injection in pregnant women. Oral levothyroxine is approved for use as a replacement therapy in hypothyroidism. There is a long experience of oral levothyroxine use in pregnant women that has not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women.

6 ADVERSE REACTIONS Adverse reactions associated with levothyroxine 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: flushing, rash Seizures have been reported rarely with the institution of levothyroxine therapy. Adverse reactions associated with Levothyroxine Sodium Injection are primarily those of hyperthyroidism due to therapeutic overdosage: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating, headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia, tremors, muscle weakness, muscle spasm, palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest, dyspnea, diarrhea, vomiting, abdominal cramps, elevations in liver function tests, flushing, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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.