Tirosint

1 INDICATION AND USAGE TIROSINT is L-thyroxine (T4) indicated for adults and pediatric patients 6 years and older with: 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 ( 1 ) Not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis ( 1 ) Hypothyroidism TIROSINT is indicated as a replacement therapy in adults and pediatric patients 6 years and older with primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression TIROSINT is indicated as an adjunct to surgery and radioiodine therapy in the management of adults and pediatric patients 6 years and older with thyrotropin-dependent well-differentiated thyroid cancer. Limitations of Use: TIROSINT 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 TIROSINT may induce hyperthyroidism [see Warnings and Precautions (5.4) ]. TIROSINT is not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis.

2 DOSAGE AND ADMINISTRATION 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 an hour of certain foods that may affect TIROSINT absorption ( 2.1 ) Swallow TIROSINT capsules whole, do not cut, crush, or chew ( 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 4-6 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 TIROSINT as a single daily oral dose, on an empty stomach, one-half to one hour before breakfast. Administer TIROSINT at least 4 hours before or after drugs known to interfere with TIROSINT absorption [see Drug Interactions (7.1) ] Evaluate the need for dose adjustments when regularly administering within an hour of certain foods that may affect TIROSINT absorption [see Drug Interactions (7.9) and Clinical Pharmacology (12.3) ]. Swallow TIROSINT capsules whole, do not cut, crush, or chew. 2.2 General Principles of Dosing The dose of TIROSINT 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 (2.4) ]. The peak therapeutic effect of a given dose of TIROSINT may not be attained for 4 to 6 weeks. 2.3 Dosing In Specific Patient Populations Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete Start TIROSINT 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 TIROSINT is approximately 1.6 mcg per kg per day (for example: 100-125 mcg per day for a 70 kg adult). Adjust the dose by 12.5 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 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 cardiovascular disease, start with a dose of 12.5 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 TIROSINT 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 to 25 mcg per day. Adjust the dose in 12.5 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 TIROSINT at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of TIROSINT dose adequacy in …

5 WARNINGS AND PRECAUTIONS Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate TIROSINT 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 TIROSINT 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 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 TIROSINT 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 TIROSINT therapy. Monitor patients receiving concomitant TIROSINT and sympathomimetic agents for signs and symptoms of coronary insufficiency . If cardiac symptoms develop or worsen, reduce the TIROSINT dose or withhold it 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 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. 5.3 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 precipitate an acute adrenal crisis in patient with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with TIROSINT [see Contraindications (4) ]. 5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism TIROSINT has a narrow therapeutic index. Over- or under-treatment with TIROSINT 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 TIROSINT 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 TIROSINT and adjust the dose as necessary [see Drug Interactions (7) and Clinical Pharmacology (12.3) ]. 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…

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

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 TIROSINT ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects thyroid hormone pharmacokinetics (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to TIROSINT (see Tables 2 to 5 below). Table 2: Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of TIROSINT 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 TIROSINT at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and TIROSINT 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 TIROSINT 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 TIROSINT 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 TIROSINT 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 …

8.1 Pregnancy Risk Summary Experience with levothyroxine 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 thyroid-stimulating hormone (TSH) levels may increase during pregnancy, TSH should be monitored and TIROSINT dosage adjusted during pregnancy [see Clinical Considerations ] . There are no animal studies conducted with levothyroxine during pregnancy. TIROSINT 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 TIROSINT requirements. Serum TSH level should be monitored and the TIROSINT dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the TIROSINT dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3) ]. Data Human Data Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have 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 TIROSINT 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 (GI): 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 associated with TIROSINT are primarily those of hyperthyroidism due to therapeutic overdosage including: 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 IBSA Pharma Inc. at 1-800-587-3513, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Adverse Reactions in Children Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children 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 GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.