Tirosint

RECENT MAJOR CHANGES Indications and Usage ( 1 ) 11/2023 Dosage and Administration ( 2.1 ) 11/2023 Dosage and Administration ( 2.2 ) 11/2023 Dosage and Administration ( 2.3 ) 11/2023 Warnings and Precautions ( 5.1 ) 11/2023 Warnings and Precautions ( 5.4 ) 11/2023

1 INDICATION AND USAGE TIROSINT-SOL is L-thyroxine (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 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-SOL 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 TIROSINT-SOL 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 Tirosint-SOL 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-SOL may induce hyperthyroidism [see Warnings and Precautions (5.1) ] . Tirosint-SOL 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, 15 minutes 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-SOL absorption ( 2.1 ) To administer TIROSINT-SOL in water, squeeze the contents of one single unit-dose ampule into a glass or cup containing water ( 2.1 ) To administer TIROSINT-SOL directly, either squeeze it into the mouth OR onto a spoon and immediately consume ( 2.1 ) Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, and 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-SOL as a single daily oral dose, on an empty stomach,15 minutes before breakfast. Administer TIROSINT-SOL at least 4 hours before or after drugs known to interfere with TIROSINT-SOL 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-SOL absorption [see Dosage and Administration (2.2 and 2.3) , Drug Interactions (7.9) and Clinical Pharmacology (12.3) ] . TIROSINT-SOL may be administered in water or directly into the mouth: To administer TIROSINT-SOL in water, squeeze the contents of one single unit-dose ampule into a glass or cup containing water. Stir the diluted TIROSINT-SOL and drink all of it immediately. Rinse the glass or cup with additional water and drink the contents to ensure that the total dose is taken. Do not dilute TIROSINT-SOL in a medium other than water. Open the ampule and prepare the solution immediately before intake. To administer TIROSINT-SOL directly (without water), either squeeze it into the mouth OR onto a spoon and immediately consume. 2.2 Important Considerations for Dosing The dosage of TIROSINT-SOL 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 dosage adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.4)] . 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 TIROSINT-SOL dosage adequacy and should not be used to monitor therapy. Use the serum free-T4 level to titrate TIROSINT-SOL 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 TIROSINT-SOL 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 TIROSINT-SOL 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 exacer …

3 DOSAGE FORMS AND STRENGTHS TIROSINT-SOL oral solution is a clear, colorless to slightly yellow solution supplied in a 1 mL white, non-transparent, unit-dose ampule. Each ampule bears a colored label with the dosage strength and the product name (TIROSINT-SOL) (Table 4). Table 4. TIROSINT-SOL Solution Strengths and Identifying Features Strength (mcg/mL) Color 13 Green 25 Orange 37.5 Dark Blue 44 Red 50 White 75 Purple 62.5 Grey 88 Olive 100 Yellow 112 Rose 125 Brown 137 Turquoise 150 Blue 175 Lilac 200 Pink Oral solution: 13, 25, 37.5, 44, 50, 62.5, 75, 88, 100, 112, 125, 137, 150, 175, 200 mcg/mL ( 3 )

4 CONTRAINDICATIONS TIROSINT-SOL is contraindicated in patients with: Hypersensitivity to glycerol, the inactive ingredient in TIROSINT-SOL [see Adverse Events (6) ]. Uncorrected adrenal insufficiency [see Warnings and Precautions (5.4) ] Hypersensitivity to glycerol ( 4 ) Uncorrected adrenal insufficiency ( 4 )

6 ADVERSE REACTIONS Adverse reactions associated with TIROSINT-SOL 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-SOL 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 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 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 GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

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-SOL ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on 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-SOL (Tables 5 to 8). Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of TIROSINT-SOL 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 TIROSINT-SOL at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and TIROSINT‐SOL for changes in thyroid function. Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol Ion Exchange Resins (e.g., Kayexalate) Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer TIROSINT-SOL at least 4 hours prior to these drugs or monitor TSH levels. Sucralfate Antacids (e.g., aluminum & magnesium hydroxides, simethicone) Gastric acidity is an essential requirement for adequate absorption of levothyroxine. However, gastric acidity may not be as essential for the absorption of TIROSINT-SOL. Sucralfate and antacids may cause hypochlorhydria, affect gastric 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 TIROSINT-SOL 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 TIROSINT-SOL 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-glucuron …

8 USE IN SPECIFIC POPULATIONS Pregnancy may require the use of higher doses of TIROSINT-SOL ( 2.3 , 8.1 ) See 17 for PATIENT COUNSELING INFORMATION and FDA‐approved patient labeling. 8.1 Pregnancy Risk Summary The clinical experience, including data from published postmarketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. 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 TIROSINT‐SOL dosage adjusted during pregnancy [see Clinical Considerations ] . Animal reproductive studies have not been conducted with levothyroxine sodium. TIROSINT-SOL 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. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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-SOL requirements. Serum TSH levels should be monitored and the TIROSINT-SOL dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the TIROSINT-SOL dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3) ]. 8.2 Lactation Risk Summary Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported and this no information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TIROSINT-SOL and any potential adverse effects on the breastfed infant from TIROSINT-SOL or from the underlying maternal condition. 8.4 Pediatric Use TIROSINT-SOL is indicated in patients from birth to less than 17 years of age: As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation. Therefore, initiate TIROSINT-SOL therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients [see Warnings and Precautions (5.1) ]. Closely monitor infants during the first two weeks of TIROSINT-SOL therapy for cardiac overload and arrhythmias. 8.5 Geriatric Use Because of the increased prevalence of cardiovascular disease among the elderly, initiate TIROSINT-SOL at less than the full replacement dose [ see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtr …

12.1 Mechanism of Action Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins. The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

11 DESCRIPTION TIROSINT-SOL (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. Levothyroxine (T4) sodium has an empirical formula of C 15 H 10 I 4 NNaO 4 ∙ x H 2 O (where x = 5), molecular weight of 798.86 g/mol (anhydrous), and structural formula as shown: TIROSINT-SOL oral solution is a clear, colorless to slightly yellow solution supplied in a 1 mL white, non-transparent, unit-dose ampule and is available in the following strengths (mcg/mL): 13, 25, 37.5, 44, 50, 62.5, 75, 88, 100, 112, 125, 137, 150, 175, 200. The inactive ingredients in TIROSINT-SOL are glycerol and water. Chemical Structure

10 OVERDOSAGE The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6) ]. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Reduce the TIROSINT-SOL dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient's medical status. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied TIROSINT-SOL (levothyroxine sodium) oral solution is a clear, colorless to slightly yellow solution supplied in a 1 mL white, non-transparent, unit-dose ampule. The dosage strength is identified on the box and the pouch, and is associated with a distinct color. Each ampule bears a colored label with the dosage strength and the product name (TIROSINT-SOL) (Table 10). Table 10. TIROSINT-SOL Solution Strengths and Packaging Description Strength (mcg/mL) Color a Box NDC (30 Unit-Dose Ampules) Pouch NDC (5 Unit-Dose Ampules) 13 Green 71858-0105-5 71858-0105-4 25 Orange 71858-0110-5 71858-0110-4 37.5 Dark Blue 71858-0112-5 71858-0112-4 44 Red 71858-0113-5 71858-0113-4 50 White 71858-0115-5 71858-0115-4 62.5 Grey 71858-0117-5 71858-0117-4 75 Purple 71858-0120-5 71858-0120-4 88 Olive 71858-0125-5 71858-0125-4 100 Yellow 71858-0130-5 71858-0130-4 112 Rose 71858-0135-5 71858-0135-4 125 Brown 71858-0140-5 71858-0140-4 137 Turquoise 71858-0145-5 71858-0145-4 150 Blue 71858-0150-5 71858-0150-4 175 Lilac 71858-0155-5 71858-0155-4 200 Pink 71858-0160-5 71858-0160-4 Storage and Handling Store TIROSINT-SOL in the original container (closed pouch) at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Use TIROSINT-SOL oral solution within three (3) months after opening the pouch. Keep the ampules in the pouch until ready to use as important information may be lost (i.e., manufacturer/distributor names and distributor contact phone number).