Levothyroxine sodium tablets, USP contain synthetic crystalline 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 15H 10I 4N NaO 4• H 2O, molecular weight of 798.86 (anhydrous), and structural formula as shown: description Levothyroxine sodium tablets, USP 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, 200 mcg, and 300 mcg. Each levothyroxine sodium tablet contains the inactive ingredients microcrystalline sodium, light magnesium oxide, sodium starch glycolate and sodium stearyl fumarate. Levothyroxine sodium tablets, USP contain no ingredients made from a gluten-containing grain (wheat, barley, or rye).

Table

6 provides a listing of the color additives by tablet strength: Table 6.

Levothyroxine Sodium Tablets Color Additives

Strength (mcg) Color additive(s) 25 FD&C Yellow No. 6 Aluminum Lake 50 None 75 FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake 88 FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 5 Aluminum Lake 100 FD&C Yellow No. 5 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake 112 FD&C Red No. 40 Aluminum Lake, Carmine 125 FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake 137 FD&C Blue No. 1 Aluminum Lake 150 FD&C Blue No. 2 Aluminum Lake 175 FD&C Blue No. 1 Aluminum Lake, Carmine 200 FD&C Red No. 40 Aluminum Lake 300 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake FDA approved dissolution test method differs from the USP dissolution test methods.

Levothyroxine sodium tablets, USP contain synthetic crystalline 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 15H 10I 4N NaO 4• H 2O, molecular weight of 798.86 (anhydrous), and structural formula as shown: description Levothyroxine sodium tablets, USP 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, 200 mcg, and 300 mcg. Each levothyroxine sodium tablet contains the inactive ingredients microcrystalline sodium, light magnesium oxide, sodium starch glycolate and sodium stearyl fumarate. Levothyroxine sodium tablets, USP contain no ingredients made from a gluten-containing grain (wheat, barley, or rye).

Table

6 provides a listing of the color additives by tablet strength: Table 6.

Levothyroxine Sodium Tablets Color Additives

Strength (mcg) Color additive(s) 25 FD&C Yellow No. 6 Aluminum Lake 50 None 75 FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake 88 FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 5 Aluminum Lake 100 FD&C Yellow No. 5 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake 112 FD&C Red No. 40 Aluminum Lake, Carmine 125 FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake 137 FD&C Blue No. 1 Aluminum Lake 150 FD&C Blue No. 2 Aluminum Lake 175 FD&C Blue No. 1 Aluminum Lake, Carmine 200 FD&C Red No. 40 Aluminum Lake 300 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake FDA approved dissolution test method differs from the USP dissolution test methods.

AND USAGE Hypothyroidism Levothyroxine sodium tablets are 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

Levothyroxine sodium tablets are 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

Levothyroxine sodium tablets are 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 levothyroxine sodium tablets may induce hyperthyroidism [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] .
Levothyroxine sodium tablets are not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. Levothyroxine sodium tablets are a 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: o Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients. o Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

AND ADMINISTRATION

Administer once daily, preferably 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 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, and concomitant medications. 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 levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half to one hour before breakfast. Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere with levothyroxine sodium absorption [see Drug Interactions (7.1) ] . Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect levothyroxine sodium tablets absorption [see Drug Interactions (7.9) and Clinical Pharmacology (12.3) ] . Administer levothyroxine sodium tablets to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL or 1 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 levothyroxine sodium tablets, such as soybean-based infant formula [see Drug Interactions (7.9) ] .

2.2 General Principles of Dosing The dose of levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets is approximately 1.6 mcg per kg per day (for example: 100 to 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 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 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of levothyroxine sodium tablets dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor adequacy of therapy in this patient population. Titrate levothyroxine sodium dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

Pediatric

Dosage - Congenital or Acquired Hypothyroidism The recommended daily dose of levothyroxine sodium tablets in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start levothyroxine sodium tablets at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0 to 3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response [see Dosage and Administration (2.4) ] .

Table

1.

Levothyroxine Sodium Tablets Dosing

Guidelines for Pediatric Hypothyroidism AGE Daily Dose Per Kg Body Weight a 0 to 3 months 10 to 15 mcg/kg/day 3 to 6 months 8 to 10 mcg/kg/day 6 to 12 months 6 to 8 mcg/kg/day 1 to 5 years 5 to 6 mcg/kg/day 6 to 12 years 4 to 5 mcg/kg/day Greater than 12 years but growth and puberty incomplete 2 to 3 mcg/kg/day Growth and puberty complete 1.6 mcg/kg/day 1. The dose should be adjusted based on clinical response and laboratory parameters [see Dosage and Administration (2.4) and Use in Specific Populations (8.4) ] . Newborns (0 to 3 months) at risk for cardiac failure : Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response. Children at risk for hyperactivity : To minimize the risk of hyperactivity in children, 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: Levothyroxine sodium tablets 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 levothyroxine sodium by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable levothyroxine sodium dose is reached and serum TSH is within the normal trimester-specific range. Reduce levothyroxine sodium dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure levothyroxine sodium dose is appropriate.

New Onset

Hypothyroidism : Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs and symptoms of hypothyroidism, start levothyroxine sodium at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH < 10 IU per litre) start levothyroxine sodium tablets at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust levothyroxine sodium tablets dosage until a serum TSH is within the normal trimester specific range [see Use in Specific Populations (8.1) ] .

Tsh

Suppression in Well-differentiated Thyroid Cancer Generally, TSH is suppressed to below

0.1 IU per litre, and this usually requires a levothyroxine sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.

2.4 Monitoring TSH and/or Thyroxine (T4)

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 levothyroxine sodium 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 levels after an interval of 6 to 8 weeks after any change in dose. 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 patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dose stabilization until growth is 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 T4 to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium therapy and/or of the serum TSH to decrease below 20 IU per litre within 4 weeks 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 levothyroxine sodium [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] . Secondary and Tertiary Hypothyroidism Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.

2.1 General Administration Information Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half to one hour before breakfast. Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere with levothyroxine sodium absorption [see Drug Interactions (7.1) ] . Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect levothyroxine sodium tablets absorption [see Drug Interactions (7.9) and Clinical Pharmacology (12.3) ] . Administer levothyroxine sodium tablets to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL or 1 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 levothyroxine sodium tablets, such as soybean-based infant formula [see Drug Interactions (7.9) ] .

2.2 General Principles of Dosing The dose of levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets is approximately 1.6 mcg per kg per day (for example: 100 to 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 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 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of levothyroxine sodium tablets dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor adequacy of therapy in this patient population. Titrate levothyroxine sodium dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

Pediatric

Dosage - Congenital or Acquired Hypothyroidism The recommended daily dose of levothyroxine sodium tablets in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start levothyroxine sodium tablets at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0 to 3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response [see Dosage and Administration (2.4) ] .

Table

1.

Levothyroxine Sodium Tablets Dosing

Guidelines for Pediatric Hypothyroidism AGE Daily Dose Per Kg Body Weight a 0 to 3 months 10 to 15 mcg/kg/day 3 to 6 months 8 to 10 mcg/kg/day 6 to 12 months 6 to 8 mcg/kg/day 1 to 5 years 5 to 6 mcg/kg/day 6 to 12 years 4 to 5 mcg/kg/day Greater than 12 years but growth and puberty incomplete 2 to 3 mcg/kg/day Growth and puberty complete 1.6 mcg/kg/day 1. The dose should be adjusted based on clinical response and laboratory parameters [see Dosage and Administration (2.4) and Use in Specific Populations (8.4) ] . Newborns (0 to 3 months) at risk for cardiac failure : Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response. Children at risk for hyperactivity : To minimize the risk of hyperactivity in children, 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: Levothyroxine sodium tablets 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 levothyroxine sodium by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable levothyroxine sodium dose is reached and serum TSH is within the normal trimester-specific range. Reduce levothyroxine sodium dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure levothyroxine sodium dose is appropriate.

New Onset

Hypothyroidism : Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs and symptoms of hypothyroidism, start levothyroxine sodium at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH < 10 IU per litre) start levothyroxine sodium tablets at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust levothyroxine sodium tablets dosage until a serum TSH is within the normal trimester specific range [see Use in Specific Populations (8.1) ] .

Tsh

Suppression in Well-differentiated Thyroid Cancer Generally, TSH is suppressed to below

0.1 IU per litre, and this usually requires a levothyroxine sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.

Primary

Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete Start levothyroxine sodium tablets 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 levothyroxine sodium tablets is approximately 1.6 mcg per kg per day (for example: 100 to 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 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 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 levothyroxine sodium tablets 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 levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of levothyroxine sodium tablets dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor adequacy of therapy in this patient population. Titrate levothyroxine sodium dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

Pediatric

Dosage - Congenital or Acquired Hypothyroidism The recommended daily dose of levothyroxine sodium tablets in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start levothyroxine sodium tablets at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0 to 3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response [see Dosage and Administration (2.4) ] .

Table

1.

Levothyroxine Sodium Tablets Dosing

Guidelines for Pediatric Hypothyroidism AGE Daily Dose Per Kg Body Weight a 0 to 3 months 10 to 15 mcg/kg/day 3 to 6 months 8 to 10 mcg/kg/day 6 to 12 months 6 to 8 mcg/kg/day 1 to 5 years 5 to 6 mcg/kg/day 6 to 12 years 4 to 5 mcg/kg/day Greater than 12 years but growth and puberty incomplete 2 to 3 mcg/kg/day Growth and puberty complete 1.6 mcg/kg/day 1. The dose should be adjusted based on clinical response and laboratory parameters [see Dosage and Administration (2.4) and Use in Specific Populations (8.4) ] . Newborns (0 to 3 months) at risk for cardiac failure : Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response. Children at risk for hyperactivity : To minimize the risk of hyperactivity in children, 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: Levothyroxine sodium tablets 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 levothyroxine sodium by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable levothyroxine sodium dose is reached and serum TSH is within the normal trimester-specific range. Reduce levothyroxine sodium dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure levothyroxine sodium dose is appropriate.

New Onset

Hypothyroidism : Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs and symptoms of hypothyroidism, start levothyroxine sodium at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH < 10 IU per litre) start levothyroxine sodium tablets at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust levothyroxine sodium tablets dosage until a serum TSH is within the normal trimester specific range [see Use in Specific Populations (8.1) ] .

Tsh

Suppression in Well-differentiated Thyroid Cancer Generally, TSH is suppressed to below

0.1 IU per litre, and this usually requires a levothyroxine sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.

2.4 Monitoring TSH and/or Thyroxine (T4)

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 levothyroxine sodium 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 levels after an interval of 6 to 8 weeks after any change in dose. 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 patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dose stabilization until growth is 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 T4 to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium therapy and/or of the serum TSH to decrease below 20 IU per litre within 4 weeks 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 levothyroxine sodium [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] . Secondary and Tertiary Hypothyroidism Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.

Adults In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8 weeks after any change in dose. 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 patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dose stabilization until growth is 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 T4 to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium therapy and/or of the serum TSH to decrease below 20 IU per litre within 4 weeks 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 levothyroxine sodium [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] .

Secondary and Tertiary Hypothyroidism Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.

CONTRAINDICATIONS Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T 3 and T 4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids (see PRECAUTIONS ).

Levothyroxine Sodium

Tablets, USP is contraindicated in patients with hypersensitivity to any of the inactive ingredients in Levothyroxine Sodium Tablets, USP. (See DESCRIPTION, Inactive Ingredients ).

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) ] .

AND PRECAUTIONS

Serious risks related to overtreatment or undertreatment with levothyroxine sodium tablets: Titrate the dose of levothyroxine sodium carefully and monitor response to titration. Error! Hyperlink reference not valid.
Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate levothyroxine sodium at less than the full replacement dose because of the increased risk of cardiac adverse reactions, including atrial fibrillation. Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid.
Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. Error! Hyperlink reference not valid.
Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement glucocorticoids prior to initiation of levothyroxine sodium treatment. Error! Hyperlink reference not valid.
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. Error! Hyperlink reference not valid.
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. Error! Hyperlink reference not valid.

5.1 Serious Risks Related to Overtreatment or Undertreatment with Levothyroxine Sodium Tablets Levothyroxine sodium tablets has a narrow therapeutic index. Overtreatment or undertreatment with levothyroxine sodium tablets may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function, and glucose and lipid metabolism in adult or pediatric patients. In pediatric patients with congenital and acquired hypothyroidism, undertreatment may adversely affect cognitive development and linear growth, and overtreatment is associated with craniosynostosis and acceleration of bone age [Use in Specific Populations (8.4) ]. Titrate the dose of levothyroxine sodium tablets carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4)]. Consider the potential for food or drug interactions and adjust the administration or dosage of levothyroxine sodium tablets as needed [see Dosage and Administration Error! Hyperlink reference not valid. , Drug Interactions Error! Hyperlink reference not valid. , and Clinical Pharmacology Error! Hyperlink reference not valid. ].

5.2 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Over-treatment 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 levothyroxine sodium therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Dosage and Administration Error! Hyperlink reference not valid. , Use in Specific Populations Error! Hyperlink reference not valid. ] . Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive levothyroxine sodium therapy. Monitor patients receiving concomitant levothyroxine sodium and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the levothyroxine sodium tablets dose or withhold for one week and restart at a lower dose.

5.3 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.

5.4 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 levothyroxine sodium [see Contraindications Error! Hyperlink reference not valid. ] .

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 discontinuing levothyroxine sodium [see Drug Interactions Error! Hyperlink reference not valid. ] .

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 levothyroxine 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 levothyroxine sodium that achieves the desired clinical and biochemical response to mitigate this risk.

5.7 Risk of Allergic Reactions Due to Tartrazine This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

5.1 Serious Risks Related to Overtreatment or Undertreatment with Levothyroxine Sodium Tablets Levothyroxine sodium tablets has a narrow therapeutic index. Overtreatment or undertreatment with levothyroxine sodium tablets may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function, and glucose and lipid metabolism in adult or pediatric patients. In pediatric patients with congenital and acquired hypothyroidism, undertreatment may adversely affect cognitive development and linear growth, and overtreatment is associated with craniosynostosis and acceleration of bone age [Use in Specific Populations (8.4) ]. Titrate the dose of levothyroxine sodium tablets carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4)]. Consider the potential for food or drug interactions and adjust the administration or dosage of levothyroxine sodium tablets as needed [see Dosage and Administration Error! Hyperlink reference not valid. , Drug Interactions Error! Hyperlink reference not valid. , and Clinical Pharmacology Error! Hyperlink reference not valid. ].

5.2 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Over-treatment 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 levothyroxine sodium therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Dosage and Administration Error! Hyperlink reference not valid. , Use in Specific Populations Error! Hyperlink reference not valid. ] . Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive levothyroxine sodium therapy. Monitor patients receiving concomitant levothyroxine sodium and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the levothyroxine sodium tablets dose or withhold for one week and restart at a lower dose.

5.3 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.

5.4 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 levothyroxine sodium [see Contraindications Error! Hyperlink reference not valid. ] .

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 discontinuing levothyroxine sodium [see Drug Interactions Error! Hyperlink reference not valid. ] .

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 levothyroxine 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 levothyroxine sodium that achieves the desired clinical and biochemical response to mitigate this risk.

5.7 Risk of Allergic Reactions Due to Tartrazine This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

7.9 Drug-Food Interactions Consumption of certain foods may affect levothyroxine sodium absorption thereby necessitating adjustments in dosing [see Dosage and Administration Error! Hyperlink reference not valid. ] . Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

7.10 Drug-Laboratory Test Interactions Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. 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.

PRECAUTIONS General Levothyroxine has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or under-treatment. These consequences include, among others, effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Many drugs interact with levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response (see Drug Interactions ). Effects on bone mineral density - In women, long-term levothyroxine sodium therapy has been associated with increased bone resorption, thereby decreasing bone mineral density, especially in post-menopausal women on greater than replacement doses or in women who are receiving suppressive doses of levothyroxine sodium. 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. Therefore, it is recommended that patients receiving levothyroxine sodium be given the minimum dose necessary to achieve the desired clinical and biochemical response. Patients with underlying cardiovascular disease - Exercise caution when administering levothyroxine to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease. In these patients, levothyroxine therapy should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease (see WARNINGS ; PRECAUTIONS, Geriatric Use ; and DOSAGE AND ADMINISTRATION ). If cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and then cautiously restarted at a lower dose. Overtreatment with levothyroxine sodium may have adverse cardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias. Patients with coronary artery disease who are receiving levothyroxine therapy should be monitored closely during surgical procedures, since the possibility of precipitating cardiac arrhythmias may be greater in those treated with levothyroxine. Concomitant administration of levothyroxine and sympathomimetic agents to patients with coronary artery disease may precipitate coronary insufficiency. Patients with nontoxic diffuse goiter or nodular thyroid disease - Exercise caution when administering levothyroxine to patients with nontoxic diffuse goiter or nodular thyroid disease in order to prevent precipitation of thyrotoxicosis (see WARNINGS ). If the serum TSH is already suppressed, levothyroxine sodium should not be administered (see Contraindications ). Associated endocrine disorders Hypothalamic/pituitary hormone deficiencies - In patients with secondary or tertiary hypothyroidism, additional hypothalamic/ pituitary hormone deficiencies should be considered, and, if diagnosed, treated (see PRECAUTIONS, Autoimmune polyglandular syndrome for adrenal insufficiency). Autoimmune polyglandular syndrome - Occasionally, chronic autoimmune thyroiditis may occur in association with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus. Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of treatment with levothyroxine sodium. Failure to do so may precipitate an acute adrenal crisis when thyroid hormone therapy is initiated, due to increased metabolic clearance of glucocorticoids by thyroid hormone. Patients with diabetes mellitus may require upward adjustments of their antidiabetic therapeutic regimens when treated with levothyroxine (see PRECAUTIONS, Drug Interactions ). Other associated medical conditions Infants with congenital hypothyroidism appear to be at increased risk for other congenital anomalies, with cardiovascular anomalies (pulmonary stenosis, atrial septal defect, and ventricular septal defect,) being the most common association. Information for Patients Patients should be informed of the following information to aid in the safe and effective use of Levothyroxine Sodium Tablets, USP: 1. Notify your physician if you are allergic to any foods or medicines, are pregnant or intend to become pregnant, are breast-feeding or are taking any other medications, including prescription and over-the-counter preparations. 2. Notify your physician of any other medical conditions you may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems. Your dose of medications used to control these other conditions may need to be adjusted while you are taking Levothyroxine Sodium Tablets, USP. If you have diabetes, monitor your blood and/or urinary glucose levels as directed by your physician and immediately report any changes to your physician. If you are taking anticoagulants (blood thinners), your clotting status should be checked frequently. 3.

Use Levothyroxine Sodium

Tablets, USP only as prescribed by your physician. Do not discontinue or change the amount you take or how often you take it, unless directed to do so by your physician. 4. The levothyroxine in Levothyroxine Sodium Tablets, USP is intended to replace a hormone that is normally produced by your thyroid gland. Generally, replacement therapy is to be taken for life, except in cases of transient hypothyroidism, which is usually associated with an inflammation of the thyroid gland (thyroiditis). 5.

Take Levothyroxine Sodium

Tablets, USP in the morning on an empty stomach, at least one-half hour to one hour before eating any food. 6. It may take several weeks before you notice an improvement in your symptoms. 7. Notify your physician if you experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event. 8. Notify your physician if you become pregnant while taking Levothyroxine Sodium Tablets, USP. It is likely that your dose of Levothyroxine Sodium Tablets, USP will need to be increased while you are pregnant. 9. Notify your physician or dentist that you are taking Levothyroxine Sodium Tablets, USP prior to any surgery. 10. Partial hair loss may occur rarely during the first few months of Levothyroxine Sodium Tablets, USP therapy, but this is usually temporary. 11.

Levothyroxine Sodium

Tablets, USP should not be used as a primary or adjunctive therapy in a weight control program. 12.

Keep Levothyroxine Sodium

Tablets, USP out of the reach of children.

Store Levothyroxine Sodium

Tablets, USP away from heat, moisture, and light. 13. Agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine sodium tablets. Therefore, levothyroxine sodium tablets should not be administered within 4 hrs of these agents.

Laboratory Tests General

The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation assay sensitivity ≤ 0.1 mlU/L or third generation assay sensitivity ≤ 0.01 mlU/L) and measurement of free-T 4 . The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. The choice of laboratory tests depends on various factors including the etiology of the underlying thyroid disease, the presence of concomitant medical conditions, including pregnancy, and the use of concomitant medications (see PRECAUTIONS, Drug Interactions and Drug-Laboratory Test Interactions ). Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of Levothyroxine Sodium Tablets, USP may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T 4 potency of the drug product. Adults In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage of levothyroxine changed, the serum TSH concentration should be measured after 8-12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6-12 months, depending on the clinical situation, and whenever there is a change in the patient's status. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving Levothyroxine Sodium Tablets, USP. (see WARNINGS , PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Pediatrics In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring both serum TSH (using a sensitive assay) and total- or free-T 4 . During the first three years of life, the serum total- or free-T 4 should be maintained at all times in the upper half of the normal range. While the aim of therapy is to also normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid feedback threshold as a result of in utero hypothyroidism. Failure of the serum T 4 to increase into the upper half of the normal range within 2 weeks of initiation of Levothyroxine Sodium Tablets, USP therapy and/or of the serum TSH to decrease below 20 mU/L within 4 weeks should alert the physician to the possibility that the child is not receiving adequate therapy. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of Levothyroxine Sodium Tablets, USP. The recommended frequency of monitoring of TSH and total or free T 4 in children is as follows: at 2 and 4 weeks after the initiation of treatment; every 1-2 months during the first year of life; every 2-3 months between 1 and 3 years of age; and every 3 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T 4 levels, and a physical examination, if indicated, be performed 2 weeks after any change in Levothyroxine Sodium Tablets, USP dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation should be performed at regular intervals (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION ). Secondary (pituitary) and tertiary (hypothalamic) hypothyroidism Adequacy of therapy should be assessed by measuring serum free-T 4 levels, which should be maintained in the upper half of the normal range in these patients.

Drug Interactions

Many drugs 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 Levothyroxine Sodium Tablets, USP. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and action of other drugs. A listing of drug-thyroidal axis interactions is contained in Table 2. The list of drug-thyroidal axis interactions in Table 2 may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware of this fact and should consult appropriate reference sources (e.g., package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected.

Table

2: Drug-Thyroidal Axis Interactions Drug or Drug Class Effect Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur Dopamine/Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). Drugs that alter thyroid hormone secretion Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents)

Lithium Methimazole

Propylthioracil (PTU)

Sulfonamides Tolbutamide

Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. Drugs that may decrease T 4 absorption, which may result in hypothyroidism Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid Drugs that may cause protein-binding site displacement Furosemide ( > 80 mg IV)

Heparin Hydantoins Non Steroidal

Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) 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 and, therefore, patients are clinically euthyroid. 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%. Drugs that may alter T 4 and T 3 metabolism Drugs that may increase hepatic metabolism, which may result in hypothyroidism Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Drugs that may decrease T 4 5' - deiodinase activity Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decrease 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. 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. 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 slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).

Miscellaneous

Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine 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 CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.

Antidiabetic

Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.

Cardiac Glycosides

Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. Cytokines - Interferon-α - Interleukin-2 Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.

Growth

Hormones - Somatrem - Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.

Ketamine

Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.

Methylxanthine

Bronchodilators - (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.

Radiographic Agents

Thyroid hormones may reduce the uptake of 123 I, 131 I, and 99m Tc.

Sympathomimetics

Concurrent use 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.

Chloral Hydrate Diazepam Ethionamide Lovastatin

Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use)

Thiazide Diuretics

These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. Oral anticoagulants - Levothyroxine 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 Levothyroxine Sodium Tablets, USP dose is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see Table 2 ). Digitalis glycosides - The therapeutic effects of digitalis glycosides may be reduced by levothyroxine. Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides (see Table 2 ). Drug-Food Interactions Consumption of certain foods may affect levothyroxine absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the GI tract. Drug-Laboratory Test Interactions Changes in TBG concentration must be considered when interpreting T 4 and T 3 values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free T 4 index (FT 4 I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or corticosteroid therapy (see also Table 2 ). Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000. Carcinogenesis, Mutagenesis, and Impairment of Fertility Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine. The synthetic T 4 in Levothyroxine Sodium Tablets, USP is identical to that produced naturally by the human thyroid gland. Although there has been a reported association between prolonged thyroid hormone therapy and breast cancer, this has not been confirmed. Patients receiving Levothyroxine Sodium Tablets, USP for appropriate clinical indications should be titrated to the lowest effective replacement dose. Pregnancy - Category A Studies in women taking levothyroxine sodium during pregnancy have not shown an increased risk of congenital abnormalities. Therefore, the possibility of fetal harm appears remote.

Levothyroxine Sodium

Tablets, USP should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, pre-eclampsia, stillbirth and premature delivery. Maternal hypothyroidism may have an adverse effect on fetal and childhood growth and development. During pregnancy, serum T 4 levels may decrease and serum TSH levels increase to values outside the normal range. Since elevations in serum TSH may occur as early as 4 weeks gestation, pregnant women taking Levothyroxine Sodium Tablets, USP should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of Levothyroxine Sodium Tablets, USP. Since postpartum TSH levels are similar to preconception values, the Levothyroxine Sodium Tablets, USP dosage should return to the pre-pregnancy dose immediately after delivery. A serum TSH level should be obtained 6-8 weeks postpartum. Thyroid hormones cross the placental barrier to some extent as evidenced by levels in cord blood of athyroceotic fetuses being approximately one third maternal levels. Transfer of thyroid hormone from the mother to the fetus, however, may not be adequate to prevent in utero, hypothyroidism.

Nursing Mothers

Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when Levothyroxine Sodium Tablets, USP is administered to a nursing woman. However, adequate replacement doses of levothyroxine are generally needed to maintain normal lactation.

Pediatric Use General

The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development. The initial dose of levothyroxine varies with age and body weight (see DOSAGE AND ADMINISTRATION , Table 3 ). Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters (see PRECAUTIONS, Laboratory Tests ). In children in whom a diagnosis of permanent hypothyroidism has not been established, it is recommended that levothyroxine administration be discontinued for a 30-day trial period, but only after the child is at least 3 years of age. Serum T 4 and TSH levels should then be obtained. If the T 4 is low and the TSH high, the diagnosis of permanent hypothyroidism is established, and levothyroxine therapy should be reinstituted. If the T 4 and TSH levels are normal, euthyroidism may be assumed and, therefore, the hypothyroidism can be considered to have been transient. In this instance, however, the physician should carefully monitor the child and repeat the thyroid function tests if any signs or symptoms of hypothyroidism develop. In this setting, the clinician should have a high index of suspicion of relapse. If the results of the levothyroxine withdrawal test are inconclusive, careful follow-up and subsequent testing will be necessary. Since some more severely affected children may become clinically hypothyroid when treatment is discontinued for 30 days, an alternate approach is to reduce the replacement dose of levothyroxine by half during the 30-day trial period. If, after 30 days, the serum TSH is elevated above 20 mU/L, the diagnosis of permanent hypothyroidism is confirmed, and full replacement therapy should be resumed. However, if the serum TSH has not risen to greater than 20 mU/L, levothyroxine treatment should be discontinued for another 30-day trial period followed by repeat serum T 4 and TSH. The presence of concomitant medical conditions should be considered in certain clinical circumstances and, if present, appropriately treated (see PRECAUTIONS ).

Congenital

Hypothyroidism (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION ) Rapid restoration of normal serum T 4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, Levothyroxine Sodium Tablets, USP therapy should be initiated immediately upon diagnosis and is generally continued for life. During the first 2 weeks of Levothyroxine Sodium Tablets, USP therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration from avid suckling. The patient should be monitored closely to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment has been associated with craniosynostosis in infants, and may adversely affect the tempo of brain maturation and accelerate the bone age with resultant premature closure of the epiphyses and compromised adult stature.

Acquired

Hypothyroidism in Pediatric Patients The patient should be monitored closely to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height.

Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, levothyroxine therapy should not be initiated at the full replacement dose (see WARNINGS , PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

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 levothyroxine sodium. (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 levothyroxine sodium (Tables 5 to 8).

Table

5.

Drugs That May

Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium 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 levothyroxine sodium tablets at least 4 hours apart from these agents.

Orlistat

Monitor patients treated concomitantly with orlistat and levothyroxine sodium 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 levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels.

Proton Pump Inhibitors Sucralfate

Antacids (e.g., 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

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 levothyroxine sodium 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 levothyroxine 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 levothyroxine.

Table

8.

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 levothyroxine sodium 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 thyroid therapy is started, changed, or discontinued [see Warnings and Precautions (5.5) ] .

7.3 Oral Anticoagulants Levothyroxine sodium 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 levothyroxine sodium dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

7.4 Digitalis Glycosides Levothyroxine sodium may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease 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 levothyroxine sodium 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. Levothyroxine sodium may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium may result in increased levothyroxine sodium requirements.

7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

7.7 Sympathomimetics Concurrent use of sympathomimetics and levothyroxine sodium 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-Food Interactions Consumption of certain foods may affect levothyroxine sodium absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1) ] . Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

7.10 Drug-Laboratory Test Interactions Thyroxine-binding Globulin (TBG) Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. 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.

Biotin

Biotin supplementation is known to interfere with thyroid hormone immunoassays that are based on a biotin and streptavidin interaction, which may result in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days prior to thyroid testing.

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 levothyroxine sodium (Tables 5 to 8).

Table

5.

Drugs That May

Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium 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 levothyroxine sodium tablets at least 4 hours apart from these agents.

Orlistat

Monitor patients treated concomitantly with orlistat and levothyroxine sodium 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 levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels.

Proton Pump Inhibitors Sucralfate

Antacids (e.g., 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

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 levothyroxine sodium 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 levothyroxine 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 levothyroxine.

Table

8.

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 levothyroxine sodium 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 thyroid therapy is started, changed, or discontinued [see Warnings and Precautions (5.5) ] .

7.3 Oral Anticoagulants Levothyroxine sodium 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 levothyroxine sodium dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

7.4 Digitalis Glycosides Levothyroxine sodium may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease 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 levothyroxine sodium 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. Levothyroxine sodium may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium may result in increased levothyroxine sodium requirements.

7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

7.7 Sympathomimetics Concurrent use of sympathomimetics and levothyroxine sodium 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.

ACTIVE INGREDIENT: Levothyroxinum 12X, 30X, 9C, 5M.

17224-504-28 Calcium stearate, dextrose, maltodextrin, mineral oil, modified wheat starch

Side Effect	Reports	% of Total	Deaths	Hosp.
Fatigue	10,494	17.0%	95	1,357
Headache	6,425	10.4%	36	1,183
Insomnia	4,663	7.6%	31	504
Drug ineffective	4,556	7.4%	73	813
Alopecia	4,491	7.3%	22	399
Weight increased	4,130	6.7%	46	399
Nausea	4,013	6.5%	44	889
Palpitations	3,825	6.2%	6	688
Dizziness	3,761	6.1%	105	687
Asthenia	3,694	6.0%	109	811
Dyspnoea	3,628	5.9%	127	1,469
Malaise	3,390	5.5%	26	798
Pain	3,220	5.2%	48	1,148
Blood thyroid stimulating hormone increased	3,171	5.1%	8	261
Arthralgia	3,165	5.1%	58	504
Diarrhoea	3,023	4.9%	65	630
Muscle spasms	3,003	4.9%	10	311
Anxiety	2,970	4.8%	81	642
Vertigo	2,732	4.4%	6	309
Feeling abnormal	2,671	4.3%	4	291

Year	Reports	Deaths	Hosp.
2000	61	0	25
2001	40	2	12
2002	39	0	19
2003	57	0	11
2004	97	40	16
2005	85	2	20
2006	83	2	20
2007	110	21	39
2008	193	18	64
2009	146	5	31
2010	180	4	42
2011	242	15	67
2012	325	34	76
2013	983	28	163
2014	1,335	69	288
2015	1,464	78	323
2016	1,654	165	490
2017	10,276	192	1,297
2018	2,361	276	705
2019	2,166	168	623
2020	2,032	240	558
2021	1,727	226	457
2022	1,341	155	307
2023	1,252	161	318
2024	813	130	182
2025	560	132	146

Indication	Reports
Product used for unknown indication	26,263
Hypothyroidism	16,969
Autoimmune thyroiditis	2,769
Thyroid disorder	2,736
Thyroidectomy	2,656
Post procedural hypothyroidism	1,154
Thyroid hormone replacement therapy	395
Basedow's disease	340
Radioactive iodine therapy	323
Thyroid cancer	299

LEVOTHYROXINE: 61,702 Adverse Event Reports & Safety Profile

What Are the Most Common LEVOTHYROXINE Side Effects?

All LEVOTHYROXINE Side Effects by Frequency

Who Reports LEVOTHYROXINE Side Effects? Age & Gender Data

Is LEVOTHYROXINE Getting Safer? Reports by Year

What Is LEVOTHYROXINE Used For?

LEVOTHYROXINE vs Alternatives: Which Is Safer?

Other Drugs in Same Class: Thyroxine [CS]

Official FDA Label for LEVOTHYROXINE

Drug Description

Table

Levothyroxine Sodium Tablets Color Additives

Table

Levothyroxine Sodium Tablets Color Additives

FDA Approved Uses (Indications)

Pituitary

Suppression

Dosage & Administration

Pediatric

Table

Levothyroxine Sodium Tablets Dosing

Pregnancy

New Onset

Tsh

0.1 IU per litre, and this usually requires a levothyroxine sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.

2.4 Monitoring TSH and/or Thyroxine (T4)

Levels

Pediatric

Table

Levothyroxine Sodium Tablets Dosing

Pregnancy

New Onset

Tsh

0.1 IU per litre, and this usually requires a levothyroxine sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.

Primary

Pediatric

Table

Levothyroxine Sodium Tablets Dosing

Pregnancy

New Onset

Tsh

0.1 IU per litre, and this usually requires a levothyroxine sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.

2.4 Monitoring TSH and/or Thyroxine (T4)

Levels

Contraindications

Levothyroxine Sodium

Known Adverse Reactions

Adverse

Hypersensitivity Reactions

FDA Boxed Warning

Warnings

Precautions

Use Levothyroxine Sodium

Take Levothyroxine Sodium

Levothyroxine Sodium

Keep Levothyroxine Sodium

Store Levothyroxine Sodium

Laboratory Tests General

Drug Interactions

Table

Lithium Methimazole

Sulfonamides Tolbutamide

Heparin Hydantoins Non Steroidal

Miscellaneous

Antidiabetic

Cardiac Glycosides

Growth

Ketamine

Methylxanthine

Radiographic Agents

Sympathomimetics

Chloral Hydrate Diazepam Ethionamide Lovastatin

Thiazide Diuretics

Levothyroxine Sodium

Nursing Mothers

Pediatric Use General

Congenital

Acquired

Geriatric Use

Drug Interactions