LEVOXYL

1 INDICATIONS AND USAGE LEVOXYL is L-thyroxine (T4) indicated in pediatric and adult patients for: Hypothyroidism: As replacement 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 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 hypothyroidism during the recovery phase of subacute thyroiditis. ( 1 ) Hypothyroidism LEVOXYL is indicated in pediatric and adult patients as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression LEVOXYL is indicated in pediatric and adult patients as an adjunct to surgery and radioiodine therapy in the management of well-differentiated thyroid cancer . Limitations of Use : LEVOXYL 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 LEVOXYL may induce hyperthyroidism [see Warnings and Precautions (5.4) ] . LEVOXYL is not indicated for treatment of 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 with a full glass of water. ( 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 absorption. ( 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 to 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 LEVOXYL tablets orally as a single daily dose, on an empty stomach, one-half to one hour before breakfast with a full glass of water to avoid choking or gagging [see Adverse Reactions (6) ]. Administer LEVOXYL at least 4 hours before or after drugs that are known to interfere with LEVOXYL absorption [see Drug Interactions (7.1) ] . Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect LEVOXYL absorption [see Drug Interactions (7.9) , Clinical Pharmacology (12.3) ]. Administer LEVOXYL to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 mL to 10 mL or 1 teaspoon to 2 teaspoons) of water and immediately administering the suspension by spoon or dropper. Do not store the suspension. Do not administer in foods that decrease absorption of LEVOXYL, such as soybean-based infant formula [see Drug Interactions (7.9) ]. 2.2 General Principles of Dosing The dose of LEVOXYL 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) , 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 LEVOXYL may not be attained for 4 to 6 weeks. 2.3 Dosing in Specific Populations Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty Are Complete Start LEVOXYL 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 LEVOXYL is approximately 1.6 mcg per kg per day (for example: 100 mcg per day to 125 mcg per day for a 70 kg adult). Adjust the dose by 12.5 mcg 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 of 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 cardiac disease, start with a dose of 12.5 mcg 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 LEVOXYL 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 mcg to 25 mcg per day. Adjust the dose in 12.5 mcg to 25 mcg increments …

3 DOSAGE FORMS AND STRENGTHS LEVOXYL tablets are oval, color-coded and, potency marked available as follows: Strength (mcg) Color Tablet Markings 25 Orange 25 50 White 50 75 Purple 75 88 Olive 88 100 Yellow 100 112 Rose 112 125 Light Brown 125 137 Dark Blue 137 150 Blue 150 175 Turquoise 175 200 Pink 200 Tablets: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg ( 3 )

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

6 ADVERSE REACTIONS Common adverse reactions with LEVOXYL therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5.4) , 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 Seizures have been reported rarely with levothyroxine therapy. Common adverse reactions for LEVOXYL 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 Pfizer, Inc. at 1-800-438-1985 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 and premature closure of the epiphysis 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. Hypersensitivity to levothyroxine itself is not known to occur. Choking and Gagging on LEVOXYL Tablets There have been reports of choking, gagging, tablet stuck in throat, and dysphagia with LEVOXYL tablets, predominately when LEVOXYL tablets were not taken with water [see Dosage and Administration (2.1) ] .

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 LEVOXYL. ( 7 ) 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 LEVOXYL (see Tables 2 – 5). Table 2: Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of LEVOXYL 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 LEVOXYL at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and LEVOXYL 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 LEVOXYL at least 4 hours prior to these drugs or monitor thyroid-stimulating hormone (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 Thyroxine (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 LEVOXYL 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 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 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 LEVOXYL 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-glucuronosyltr …

8 USE IN SPECIFIC POPULATIONS Pregnancy may require the use of higher doses of levothyroxine. ( 2.3 , 8.1 ) 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 LEVOXYL dosage adjusted during pregnancy (see Clinical Considerations ). There are no animal studies conducted with levothyroxine during pregnancy. LEVOXYL 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 LEVOXYL requirements. Serum TSH level should be monitored and the LEVOXYL dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the LEVOXYL 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. 8.2 Lactation Risk Summary Limited published studies report that levothyroxine is present in human milk. However, there is insufficient information to determine the effects of levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LEVOXYL and any potential adverse effects on the breastfed infant from LEVOXYL or from the underlying maternal condition. 8.4 Pediatric Use The initial dose of LEVOXYL varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters [see Dosage and Administration (2.3 , 2.4) ] . In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue LEVOXYL for a trial period, but only after the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, and use laboratory test results and clinical assessments to guide diagnosis and treatment, if warranted. Congenital Hypothyroidism [see Dosage and Administration (2.3 , 2.4) ] Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate LEVOXYL therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients. Closely monitor infants during the first 2 weeks of LEVOXYL therapy for cardiac overload, arrhythmias, and aspiration from avid suckling. Clo …

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 LEVOXYL contains the active ingredient, levothyroxine, asynthetic crystalline levothyroxine (T4) in sodium salt form. It is chemically designated as L-3,3',5,5'-tetraiodothyronine monosodium hydrate. Synthetic T4 is identical in chemical structure to the T4 produced in the human thyroid gland. Levothyroxine sodium has an empirical formula of C 15 H 10 I 4 N NaO 4 ∙ H 2 O, molecular weight of 798.85 g/mol (anhydrous), and structural formula as shown: LEVOXYL tablets for oral administration are supplied in the following strengths: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, and 200 mcg. Chemical Structure Inactive Ingredients Calcium sulfate dihydrate, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate. The following are the coloring additives per tablet strength: Strength (mcg) Color additive(s) 25 FD&C Yellow No. 6 Aluminum Lake 50 None 75 FD&C Blue No. 1 Aluminum Lake, D&C Red No. 30 Aluminum Lake 88 FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake 100 FD&C Yellow No. 6 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake 112 FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, D&C Red No. 30 Aluminum Lake 125 FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake 137 FD&C Blue No. 1 Aluminum Lake 150 FD&C Blue No. 1 Aluminum Lake, D&C Red No. 30 Aluminum Lake 175 FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake 200 D&C Red No. 30 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake

10 OVERDOSAGE The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5.4) , 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 LEVOXYL dose or temporarily discontinued 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 LEVOXYL (levothyroxine sodium) tablets are oval, color-coded and, potency marked available as follows: Strength (mcg) Color Tablet Markings NDC - bottles of 100 NDC - bottles of 1000 25 Orange 25 60793-850-01 60793-850-10 50 White 50 60793-851-01 60793-851-10 75 Purple 75 60793-852-01 60793-852-10 88 Olive 88 60793-853-01 60793-853-10 100 Yellow 100 60793-854-01 60793-854-10 112 Rose 112 60793-855-01 60793-855-10 125 Light Brown 125 60793-856-01 60793-856-10 137 Dark Blue 137 60793-857-01 60793-857-10 150 Blue 150 60793-858-01 60793-858-10 175 Turquoise 175 60793-859-01 60793-859-10 200 Pink 200 60793-860-01 60793-860-10 STORAGE CONDITIONS Store between 68°F–77°F (20°C–25°C) with excursions permitted between 59°F–86°F (15°C–30°C). Store LEVOXYL away from heat, moisture, and light.