PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Package/Label Display Panel

Levothyroxine Sodium Tablet USP

175 mcg (0.175 mg)

100 Tablets

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RECENT MAJOR CHANGES SECTION

Highlight: Indications and Usage (1) 8/2022

Dosage and Administration (2.2) 8/2022

Dosage and Administration (2.3) 8/2022

Warnings and Precautions (5.1) 8/2022

Warnings and Precautions (5.4) 8/2022

RECENT MAJOR CHANGES

Indications and Usage (1) 8/2022

Dosage and Administration (2.2) 8/2022

Dosage and Administration (2.3) 8/2022

Warnings and Precautions (5.1) 8/2022

Warnings and Precautions (5.4) 8/2022

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DESCRIPTION SECTION

11 DESCRIPTION

Levothyroxine sodium tablets USP is L-thyroxine (T4) and contains synthetic crystalline L-3,3',5,5' tetraiodothyronine sodium salt. Synthetic T4 is chemically identical to that produced in the human thyroid gland. Levothyroxine (T4) sodium has an empirical formula of C15H10I4N NaO4•xH2O, molecular weight of 798.85 (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 tablets USP contains the inactive ingredients corn starch, croscarmellose sodium, magnesium stearate, mannitol and sodium bicarbonate. Table 9 provides a listing of the color additives by tablet strength:

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.

The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

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 tablets 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 T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption [see Drug Interactions (7)].

Distribution

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 [see Drug Interactions (7)]. Thyroid hormones do not readily cross the placental barrier [see Use in Specific Populations (8.1)].

Elimination

Metabolism

T4 is slowly eliminated (see Table 10). 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.

Excretion

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

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INDICATIONS & USAGE SECTION

Highlight: Levothyroxine sodium tablet is a L-thyroxine (T4) indicated in adult and pediatric patients, including neonates, for:

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Hypothyroidism: As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. (1)

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Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. (1)

Limitations of Use

•

Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients.

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Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

1 INDICATIONS 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 (5.1)].

•

Levothyroxine sodium tablets are not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

DOSAGE & ADMINISTRATION SECTION

Highlight: •

Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast. (2.1)

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Administer at least 4 hours before or after drugs that are known to interfere with absorption. (2.1)

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Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect absorption. (2.1)

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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)

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See full prescribing information for dosing in specific patient populations. (2.3)

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Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status. (2.4)

2 DOSAGE AND ADMINISTRATION

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.

Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere with levothyroxine sodium tablets absorption [see Drug Interactions (7.1)].

Evaluate the need for dosage adjustments when regularly administering within one hour of certain foods that may affect levothyroxine sodium tablets absorption [see Dosage and Administration (2.2 and 2.3), Drug Interactions (7.9) and Clinical Pharmacology (12.3)].

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 [see Drug Interactions (7.9)].

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 [see Dosage and Administration (2.3), Warnings and Precautions (5), and Drug Interactions (7)]. Dosing must be individualized to account for these factors and dosage adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.4)].

For adult patients with primary hypothyroidism, titrate until the patient is clinically euthyroid and the serum TSH returns to normal [see Dosage and Administration (2.3)].

For secondary or tertiary hypothyroidism, serum TSH is not a reliable measure of levothyroxine sodium tablets 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 [see Dosage and Administration (2.3)].

The peak therapeutic effect of a given dose of levothyroxine sodium tablets may not be attained for 4 to 6 weeks.

2.3 Recommended Dosage and Titration

Primary, Secondary, and Tertiary Hypothyroidism in Adults

The recommended starting daily dosage of 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 [see Dosage and Administration (2.2)].

Table 1. Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Adults*

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 [see Dosage and Administration (2.2)].

Table 2. Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Pediatric Patients

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 4 to 6 weeks as needed based on clinical and laboratory response.

Pediatric Patients at Risk for Hyperactivity

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.

Hypothyroidism in Pregnant Patients

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 Tablets Dosing guidelines for Hypothyroidism in Pregnant Patients

TSH Suppression in Well-differentiated Thyroid Cancer in Adult and Pediatric Patients

The levothyroxine sodium tablets 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. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of levothyroxine sodium tablets 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 dosage. In patients on a stable and appropriate replacement dosage, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient's clinical status.

Pediatric Patients

In patients with 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 pediatric patients 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 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 tablets therapy and/or of the serum TSH to decrease below 20 IU per liter 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 tablets [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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Tablets: 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 mcg (3)

3 DOSAGE FORMS AND STRENGTHS

Levothyroxine sodium tablets USP are round, colored, scored and debossed with following debossing details on one side and break-line on other side. They are available as follows (Table 4)

Table 4: Levothyroxine Sodium Tablet Strengths and Identifying Features

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CONTRAINDICATIONS SECTION

Highlight: •

Uncorrected adrenal insufficiency. (4)

4 CONTRAINDICATIONS

Levothyroxine sodium tablets are contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (5.4)].

Boxed Warning section

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

See full prescribing information for complete boxed warning

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**Thyroid hormones, including levothyroxine sodium tablet should not be used for the treatment of obesity or for weight loss.**

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**Doses beyond the range of daily hormonal requirements may produce serious or even life-threatening manifestations of toxicity (****6****,****10****).**

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: Pregnancy may require the use of higher doses of levothyroxine sodium tablets. (2.3, 8.1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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. Since TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine sodium tablets dosage adjusted during pregnancy (see Clinical Considerations). Animal reproductive studies have not been conducted with levothyroxine sodium. Levothyroxine sodium tablets should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre- eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development.

Dose Adjustments During Pregnancy and the Postpartum Period

Pregnancy may increase levothyroxine sodium tablets requirements. Serum TSH levels should be monitored and the levothyroxine sodium tablets dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the levothyroxine sodium tablets dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3)].

8.2 Lactation

Risk Summary

Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported and 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 tablets and any potential adverse effects on the breastfed infant from levothyroxine sodium tablets or from the underlying maternal condition.

8.4 Pediatric Use

Levothyroxine Sodium Tablets is indicated in patients from birth to less than 17 years of age:

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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 tablets therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients. [see Warnings and Precautions (5.1)].

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

8.5 Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium tablets at less than the full replacement dose [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

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OVERDOSAGE SECTION

10 OVERDOSAGE

The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

Reduce the levothyroxine sodium tablets 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 www.poison.org.

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Inform the patient of the following information to aid in the safe and effective use of****levothyroxine sodium tablets:

Dosing and Administration

•

Instruct patients to take levothyroxine sodium tablets only as directed by their healthcare provider.

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Instruct patients to take levothyroxine sodium tablets as a single dose, preferably on an empty stomach, one-half to one hour before breakfast.

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Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine. Instruct patients not to take levothyroxine sodium tablets within 4 hours of these agents.

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Instruct patients to notify their healthcare provider if they are pregnant or breastfeeding or are thinking of becoming pregnant while taking levothyroxine sodium tablets.

Important Information

•

Inform patients that it may take several weeks before they notice an improvement in symptoms.

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Inform patients that the levothyroxine in levothyroxine sodium tablet is intended to replace a hormone that is normally produced by the thyroid gland. Generally, replacement therapy is to be taken for life.

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Inform patients that levothyroxine sodium tablets should not be used as a primary or adjunctive therapy in a weight control program.

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Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations.

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Instruct patients to notify their physician of any other medical conditions they may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking levothyroxine sodium tablets. If they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. If patients are taking anticoagulants, their clotting status should be checked frequently.

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Instruct patients to notify their physician or dentist that they are taking levothyroxine sodium tablets prior to any surgery.

Adverse Reactions

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Instruct patients to notify their healthcare provider if they 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.

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Inform patients that partial hair loss may occur rarely during the first few months of levothyroxine sodium tablets therapy, but this is usually temporary.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Pithampur (M.P.) - 454 775

INDIA

Packaged and Distributed by:

MAJOR® PHARMACEUTICALS

Indianapolis, IN 46268 USA

Refer to package label for Distributor's NDC Number

Revised: September 2023 ID#: 274663

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Levothyroxine sodium tablets USP are round, colored, scored and debossed with following debossing details on one side and break-line on other side. They are supplied as follows:

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Levothyroxine sodium tablets USP should be protected from light and moisture.

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