LEVOTIRON

Levothyroxine sodium tablets, USP is L-thyroxine (T4) and contains synthetic crystalline L-3,3’,5,5’-tetraiodothyronine sodium salt.

T4 is chemically identical to that produced in the human thyroid gland.

Levothyroxine (T4) sodium has an empirical formula of C 15 H 10 I 4 N NaO 4.

• H 2 O, molecular weight of 798.86 (anhydrous), and structural formula as shown: 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 9 provides a listing of the color additives by tablet strength: Table 9.

Strength (mcg) Color additive(s) 25 FD&C Yellow No.

Lake 50 None 75 FD&C Red No.

Lake 88 FD&C Blue No.

Lake 100 FD&C Yellow No.

Lake 112 FD&C Red No.

Lake, Carmine 125 FD&C Yellow No.

Lake 137 FD&C Blue No.

Lake 150 FD&C Blue No.

Lake 175 FD&C Blue No.

Lake, Carmine 200 FD&C Red No.

Lake 300 D&C Yellow No.

Levothyroxine sodium tablets, USP meets USP Dissolution Test 7. description.

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.

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.

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 may induce hyperthyroidism.

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.

Thyrotropin (Thyroid‑Stimulating Hormone, TSH) Suppression: As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

Lactation Angor Anorexia History of epilepsy

History of cardiovascular disease Recent history of myocardial infarction Arrhythmia Atherosclerosis Thyroid gland autonomy Diabetes Child with swallowing difficulties Menopausal woman Goiter Large goiter Pregnancy Hypertension Hyperthyroidism Hypopituitarism Chronic hypothyroidism Secondary hypothyroidism Severe hypothyroidism Heart failure Coronary heart failure Surreal impairment Interchangeability Myocarditis Infants under 30 months of age Low-weight newborn Postpartum Premature Elderly Subject at risk of psychiatric illness Low weight Subject undernourished Tachyarrhythmia Tachycardia.

Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis.

Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA.

This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.

The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues. 12.2 Pharmacodynamics Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as endogenous T4, thereby maintaining normal T4 levels when a deficiency is present. 12.3 Pharmacokinetics Absorption Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%.

The majority of the levothyroxine sodium dose is absorbed from the jejunum and upper ileum.

The relative bioavailability of levothyroxine sodium tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%.

T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans.

Dietary fiber decreases bioavailability of

Absorption may also decrease with age.

In addition, many drugs and foods affect T4 absorption.

Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone.

The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3.

Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone.

Only unbound hormone is metabolically active.

Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins.

Thyroid hormones do not readily cross the placental barrier.

T4 is slowly eliminated.

The major pathway of thyroid hormone metabolism is through sequential deiodination.

Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination.

The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues.

Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3).

T3 and rT3 are further deiodinated to diiodothyronine.

Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.

Thyroid hormones are primarily eliminated by the kidneys.

A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces.

Approximately 20% of T4 is eliminated in the stool.

Urinary excretion of

T4 decreases with age.

Table 10.

Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency t 1/2 (days) Protein Binding (%) Levothyroxine (T4) 10 to 20 1 6 to 7 99.96 Liothyronine (T3) 1 4 ≤ 2 99.5 Includes TBG, TBPA, and TBA ** 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism.

• Hypercalcuria Hypersudation Subcutaneous tissue disorders Rash Hyperhidrosis Pruritus
• Skin Erythema Alopecia Urticaria Allergic dermatitis Fever Heat tolerance Hyperthyroidism (Common)
• Menstrual disorder Hypersensitivity Angioedema Appetite increased Weight (decrease)
• Insomnia (Very common)
• Nervousness (Common)
• Agitation Tachycardia (Common)
• Palpitation (Very common)
• Atrial fibrillation Cardiovascular collapsus Congestive puff Cardiopathies (aggravation)
• Myocardial infarction Angor Hypertension Arrhythmia Extrasystole Craniostenosis Heart failure
• Vomiting Nausea Abdominal pain Diarrhoea Cramp Premature welding of epiphyses Muscle weakness
• Osteoporosis Headache (Very common)
• Brain Pseudomeur (Rare)
• Intracranial hypertension
• Trembling Respiratory allergy symptom Dyspnoea.

The signs and symptoms of overdosage are those of hyperthyroidism.

In addition, confusion and disorientation may occur.

Cerebral embolism, shock, coma, and death have been reported.

Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine.

Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

Reduce the levothyroxine sodium dosage or discontinue temporarily if signs or symptoms of overdosage occur.

Initiate appropriate supportive treatment as dictated by the patient’s medical status.

For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or.

Levothyroxine sodium tablets are contraindicated in patients with uncorrected adrenal insufficiency.

Uncorrected adrenal insufficiency.

Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast with a full glass of water.

Administer at least 4 hours before or after drugs that are known to interfere with absorption.

Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect absorption.

Advise patients to stop biotin and biotin-containing supplements at least 2 days before assessing TSH and/or T4 levels.

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 to 6 weeks.

See full prescribing information for dosing in specific patient populations.

Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status. 2.1 Important Administration Instructions Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half to one hour before breakfast with a full glass of water to avoid choking or gagging.

Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere with levothyroxine sodium absorption.

Evaluate the need for dosage adjustments when regularly administering within one hour of certain foods that may affect levothyroxine sodium tablets absorption.

Administer levothyroxine sodium tablets to pediatric patients who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL) of water and immediately administering the suspension by spoon or dropper.

Ensure the patient ingests the full amount of the suspension.

Do not store the suspension.

Do not administer in foods that decrease absorption of levothyroxine sodium tablets, such as soybean-based infant formula. 2.2 Important Considerations for Dosing The dosage 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.

Dosing must be individualized to account for these factors and dosage adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters.

For adult patients with primary hypothyroidism, titrate until the patient is clinically euthyroid and the serum TSH returns to normal.

For secondary or tertiary hypothyroidism, serum TSH is not a reliable measure of levothyroxine sodium dosage adequacy and should not be used to monitor therapy.

Use the serum free-T4 level to titrate levothyroxine sodium tablets dosing until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

Inquire whether patients are taking biotin or biotin-containing supplements.

If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels.

The peak therapeutic effect of a given dose of levothyroxine sodium tablets may not be attained for to 6 weeks. 2.3 Recommended Dosage and Titration Primary, Secondary, and Tertiary Hypothyroidism in Adults The recommended starting daily dosage of levothyroxine sodium tablets in adults with primary, secondary, or tertiary hypothyroidism is based on age and comorbid cardiac conditions, as described in Table 1.

For patients at risk of atrial fibrillation or patients with underlying cardiac disease, start with a lower dosage and titrate the dosage more slowly to avoid exacerbation of cardiac symptoms.

Dosage titration is based on serum

TSH or free-T4.

Table 1.

Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Adults Dosages greater than 200 mcg/day are seldom required.

An inadequate response to daily dosages greater than 300 mcg/day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.

Patient Population Starting Dosage Dosage Titration Based on serum TSH or Free-T4 Adults diagnosed with hypothyroidism Full replacement dose is 1.6 mcg/kg/day. Some patients require a lower starting dose.

Titrate dosage by 12.5 to 25 mcg increments every to 6 weeks, as needed until the patient is euthyroid.

Adults at risk for atrial fibrillation or with underlying cardiac disease Lower starting dose (less than 1.6 mcg/kg/day) Titrate dosage every to 8 weeks, as needed until the patient is euthyroid.

Geriatric patients

Lower starting dose (less than 1.6 mcg/kg/day) Primary, Secondary, and Tertiary Hypothyroidism in Pediatric Patients The recommended starting daily dosage of levothyroxine sodium tablets in pediatric patients with primary, secondary, or tertiary hypothyroidism is based on body weight and changes with age as described in Table 2.

Titrate the dosage (every 2 weeks) as needed based on serum TSH or free-T4 until the patient is euthyroid.

Table 2.

Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Pediatric Patients Age Starting Daily Dosage Per Kg Body Weight 0 to 3 months to 15 mcg/kg/day to 6 months to 10 mcg/kg/day to 12 months to 8 mcg/kg/day to 5 years to 6 mcg/kg/day to 12 years to 5 mcg/kg/day Greater than 12 years but growth and puberty incomplete to 3 mcg/kg/day Growth and puberty complete 1.6 mcg/kg/day Adjust dosage based on clinical response and laboratory parameters.

Pediatric Patients from

Birth to 3 Months of Age at Risk for Cardiac Failure Start at a lower starting dosage and increase the dosage every to 6 weeks as needed based on clinical and laboratory response.

To minimize the risk of hyperactivity, start at one-fourth the recommended full replacement dosage, and increase on a weekly basis by one-fourth the full recommended replacement dosage until the full recommended replacement dosage is reached.

For pregnant patients with pre-existing hypothyroidism, measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy.

In pregnant patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range.

The recommended daily dosage of levothyroxine sodium tablets in pregnant patients is described in Table 3.

Table 3.

Levothyroxine Sodium Tablet Dosing Guidelines for Hypothyroidism in Pregnant Patients Patient Population Starting Dosage Dose Adjustment and Titration Pre-existing primary hypothyroidism with serum TSH above normal trimester.

• specific range Pre-pregnancy dosage may increase during pregnancy Increase levothyroxine sodium dosage by 12.5 to 25 mcg per day. Monitor TSH every 4 weeks until a stable dose is reached and serum TSH is within normal trimester-specific range.

Reduce levothyroxine sodium dosage to pre-pregnancy levels immediately after delivery.

Monitor serum

TSH to 8 weeks postpartum.

New onset hypothyroidism (TSH ≥10 mIU per liter) 1.6 mcg/kg/day Monitor serum TSH every 4 weeks and adjust levothyroxine sodium dosage until serum TSH is within normal trimester-specific range.

New onset hypothyroidism (TSH < 10 mIU per liter) 1.0 mcg/kg/day TSH Suppression in Well-differentiated Thyroid Cancer in Adult and Pediatric Patients The levothyroxine sodium dosage is based on the target level of TSH suppression for the stage and clinical status of thyroid cancer. 2.4 Monitoring TSH and/or Thyroxine (T4) Levels Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation.

Biotin supplementation may interfere with immunoassays for TSH, T4, and T3, resulting in erroneous thyroid hormone test results.

Stop biotin and biotin-containing supplements for at least 2 days before assessing TSH and/or T4 levels.

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.

In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of to 8 weeks after any change in dosage.

In patients on a stable and appropriate replacement dosage, evaluate clinical and biochemical response every to 12 months and whenever there is a change in the patient’s clinical status.

In patients with hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4.

TSH and total or free-T4 in pediatric patients as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every to 12 months thereafter following dosage 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.

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 mIU per litre within 4 weeks may indicate the patient is not receiving adequate therapy.

Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of levothyroxine sodium.

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

50090-6115 NDC: 50090-6115-0 30 TABLET in a BOTTLE NDC: 50090-6115-1 90 TABLET in a BOTTLE.

The clinical experience, including data from postmarketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy.

TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine sodium dosage adjusted during pregnancy.

Animal reproductive studies have not been conducted with levothyroxine sodium.

Levothyroxine sodium should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Maternal and/or Embryo/Fetal Risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre‑eclampsia, stillbirth, and premature delivery.

Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development.

Dose Adjustments During Pregnancy and the Postpartum Period Pregnancy may increase levothyroxine sodium requirements.

TSH levels should be monitored and the levothyroxine sodium dosage adjusted during pregnancy.

Since postpartum

TSH levels are similar to preconception values, the levothyroxine sodium dosage should return to the pre-pregnancy dose immediately after delivery.

Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine.

No adverse effects on the breastfed infant have been reported and there is no information on the effects of levothyroxine on milk production.

Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levothyroxine sodium and any potential adverse effects on the breastfed infant from levothyroxine sodium or from the underlying maternal condition.

Levothyroxine sodium is indicated in patients from birth to less than 17 years of age: As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Rapid restoration of normal serum

T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation.

Therefore, initiate levothyroxine sodium therapy immediately upon diagnosis.

Levothyroxine is generally continued for life in these patients.

Closely monitor infants during the first 2 weeks of levothyroxine sodium therapy for cardiac overload and arrhythmias.

Because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium at less than the full replacement dose.

Atrial arrhythmias can occur in elderly patients.

Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.