NDC 70934-382 Levothyroxine Sodium

Levothyroxine Sodium

NDC Product Code 70934-382

NDC Code: 70934-382

Proprietary Name: Levothyroxine Sodium What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Levothyroxine Sodium What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
ORANGE (C48331 - PEACH)
GREEN (C48329 - OLIVE)
YELLOW (C48330)
PINK (C48328 - ROSE)
BROWN (C48332 - TAN)
BLUE (C48333)
Shape: ROUND (C48348)
Size(s):
6 MM
Imprint(s):
L15
L19
L20
L21
L22
L24
Score: 2

NDC Code Structure

  • 70934 - Denton Pharma, Inc. Dba Northwind Pharmaceuticals

NDC 70934-382-90

Package Description: 90 TABLET in 1 BOTTLE, PLASTIC

NDC Product Information

Levothyroxine Sodium with NDC 70934-382 is a a human prescription drug product labeled by Denton Pharma, Inc. Dba Northwind Pharmaceuticals. The generic name of Levothyroxine Sodium is levothyroxine sodium. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Denton Pharma, Inc. Dba Northwind Pharmaceuticals

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Levothyroxine Sodium Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • LEVOTHYROXINE SODIUM .15 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM BICARBONATE (UNII: 8MDF5V39QO)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • FD&C BLUE NO. 1 (UNII: H3R47K3TBD)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM BICARBONATE (UNII: 8MDF5V39QO)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM BICARBONATE (UNII: 8MDF5V39QO)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • D&C RED NO. 27 (UNII: 2LRS185U6K)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM BICARBONATE (UNII: 8MDF5V39QO)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • FD&C BLUE NO. 1 (UNII: H3R47K3TBD)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • FD&C RED NO. 40 (UNII: WZB9127XOA)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM BICARBONATE (UNII: 8MDF5V39QO)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM BICARBONATE (UNII: 8MDF5V39QO)
  • STARCH, CORN (UNII: O8232NY3SJ)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • l-Thyroxine - [EPC] (Established Pharmacologic Class)
  • Thyroxine - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Denton Pharma, Inc. Dba Northwind Pharmaceuticals
Labeler Code: 70934
FDA Application Number: ANDA209713 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 06-04-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Levothyroxine Sodium Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Not For Treatment Of Obesity Or For Weight Loss

Thyroid hormones, including levothyroxine sodium tablets, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects


[see Adverse Reactions (


6), Drug Interactions (


7.7), and Overdosage (


10)]


.

1 Indications And Usage

  • HypothyroidismLevothyroxine sodium tablets are indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) SuppressionLevothyroxine sodium tablets are indicated 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 (
  • 5.4)]
  • .
  • Levothyroxine sodium tablets are not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

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 tablets 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 CompleteStart 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 HypothyroidismStart 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 tablets 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 HypothyroidismThe 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 HypothyroidismAGEDaily Dose Per Kg Body Weight


 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)].
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


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.


PregnancyPre-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 tablets by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable levothyroxine sodium tablets dose is reached and serum TSH is within the normal trimester-specific range. Reduce levothyroxine sodium tablets dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure levothyroxine sodium tablets 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 tablets at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH < 10 IU per liter) 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 CancerGenerally, TSH is suppressed to below 0.1 IU per liter, 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 tablets may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors.AdultsIn 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.PediatricsIn 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 tablets therapy and/or of the serum TSH to decrease below 20 IU per liter 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 tablets


[see Warnings and Precautions (


5.1) and Use in Specific Populations (


8.4)]


.


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

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 supplied as follows:Tablet StrengthTablet Color/ShapeDebossing Details25 mcg


Peach/Round


L15


50 mcg


White/Round


L16


75 mcg


Violet/Round


L17


88 mcg


Olive/Round


L19


100 mcg


Yellow/Round


L20


112 mcg


Rose/Round


L21


125 mcg


Tan/Round


L22


137 mcg


Turquoise/Round


L23


150 mcg


Blue/Round


L24


175 mcg


Lilac/Round


L25


200 mcg


Pink/Round


L26


300 mcg


Green/Round


L27

4 Contraindications

Levothyroxine sodium tablets are contraindicated in patients with uncorrected adrenal insufficiency


[see Warnings and Precautions (


5.3)]


.

5.1 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 tablets therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease


[see Dosage and Administration (


2.3), Use in Specific Populations (


8.5)]


.


Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive levothyroxine sodium tablets therapy. Monitor patients receiving concomitant levothyroxine sodium tablets 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.

5.2 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.

5.3 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 tablets


[see Contraindications (


4)]


.

5.4 Prevention Of Hyperthyroidism Or Incomplete Treatment Of Hypothyroidism

Levothyroxine sodium tablet has a narrow therapeutic index. Over- or undertreatment with levothyroxine sodium tablets may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and glucose and lipid metabolism. Titrate the dose of levothyroxine sodium tablets carefully and monitor response to titration to avoid these effects


[see Dosage and Administration (


2.4)]


. Monitor for the presence of drug or food interactions when using levothyroxine sodium tablets and adjust the dose as necessary


[see Drug Interactions (


7.9) and Clinical Pharmacology (


12.3)]


.

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 tablets


[see Drug Interactions (


7.2)]


.

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

6 Adverse Reactions

  • Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of hyperthyroidism due to therapeutic overdosage
  • [see Warnings and Precautions (
  • 5), Overdosage (
  • 10)]
  • . They include the following:
  • General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating
  • Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia
  • Musculoskeletal: tremors, muscle weakness, muscle spasm
  • Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest
  • Respiratory: dyspnea
  • Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests
  • Dermatologic: hair loss, flushing, rash
  • Endocrine: decreased bone mineral density
  • Reproductive: menstrual irregularities, impaired fertility
  • Seizures have been reported rarely with the institution of levothyroxine therapy.Adverse Reactions in ChildrenPseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.Hypersensitivity ReactionsHypersensitivity 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.

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 tablets (see Tables 2 to 5 below).Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)\Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium tablets by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.


Drug or Drug ClassEffectCalcium Carbonate


Ferrous Sulfate


Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine sodium tablets at least 4 hours apart from these agents.


Orlistat


Monitor patients treated concomitantly with orlistat and levothyroxine sodium tablets for changes in thyroid function.


Bile Acid Sequestrants


-Colesevelam


-Cholestyramine


-Colestipol


Ion Exchange Resins


-Kayexalate


-Sevelamer


Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels.


Other drugs:


Proton Pump Inhibitors


Sucralfate


Antacids


- Aluminum & Magnesium Hydroxides


- Simethicone


Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.


Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)Drug or Drug ClassEffectClofibrate


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 tablets 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 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine sodium tablets requirements.


Drug or Drug ClassEffectPhenobarbital 


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 5. Drugs That May Decrease Conversion of T4 to T3Potential 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 ClassEffectBeta-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 tablets 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 tablet 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 dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

7.4 Digitalis Glycosides

Levothyroxine sodium tablets 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 tablets 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 tablets may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium tablets may result in increased levothyroxine sodium tablets requirements.

7.6 Ketamine

Concurrent use of ketamine and levothyroxine sodium tablets 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 tablets 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 tablets 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 tablets 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.

8.1 Pregnancy

Risk SummaryExperience with levothyroxine use in pregnant women, including data from post-marketing studies, have not reported increased rates of major birth defects or miscarriages


[see Data]. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine sodium tablets dosage adjusted during pregnancy


[see Clinical Considerations]. There are no animal studies conducted with levothyroxine during pregnancy. 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. 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskMaternal 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 PeriodPregnancy 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)]


.


DataHuman DataLevothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women.

8.2 Lactation

Risk SummaryLimited published studies report that levothyroxine is present in human milk. However, there is insufficient information to determine the effects of levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for 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

The initial dose of levothyroxine sodium tablets varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters


[see Dosage and Administration (


2.3,


2.4)]


.


In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue levothyroxine sodium tablets administration for a trial period, but only after the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, and use laboratory test results and clinical assessment to guide diagnosis and treatment, if warranted.Congenital Hypothyroidism 


[See Dosage and Administration (


2.3,


2.4)]


Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate levothyroxine sodium tablets therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients.Closely monitor infants during the first 2 weeks of levothyroxine sodium tablets therapy for cardiac overload, arrhythmias, and aspiration from avid suckling.Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.Acquired Hypothyroidism in Pediatric PatientsClosely monitor patients 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.

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 Warnings and Precautions (


5.1) and Dosage and Administration (


2.3)]


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

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 dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient's medical status.For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

11 Description

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•xH


2O, 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 6 provides a listing of the color additives by tablet strength: Strength (mcg) Color additive(s) 25


FD&C Yellow No. 6 Aluminum Lake


Note – FD&C Yellow No. 6 is peach in color. 50


FD&C Blue 1 Aluminum Lake


75


FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake


88


FD&C Yellow No. 6 Aluminum Lake


, FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake


100


FD&C Yellow No. 6 Aluminum Lake


, D&C Yellow No. 10 Aluminum Lake


112


D&C Red No 27 Aluminum Lake


125


FD&C Yellow No. 6 Aluminum Lake


, FD&C Blue No. 1 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 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, D&C Red No. 27 Aluminum Lake


200


FD&C Red No. 40 Aluminum Lake


300


FD&C Yellow No. 6 Aluminum Lake


, FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake

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

AbsorptionAbsorption 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)]


.


DistributionCirculating 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)]


.


EliminationMetabolismT4 is slowly eliminated (see Table 7). 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.ExcretionThyroid 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 7. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid PatientsHormoneRatio in ThyroglobulinBiologic Potencyt


1/2 


(days)Protein Binding (%)Includes TBG, TBPA, and TBALevothyroxine (T4)


10 to 20


1


6 to 7


3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism99.96


Liothyronine (T3)


1


4


≤ 2


99.5

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Standard animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine.

16 How Supplied/Storage And Handling

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:Strength (mcg)Color/ShapeDebossing DetailsNDC# for bottles of 90NDC # for bottles of 100NDC # for bottles of 500NDC # for bottles of 100025


Peach/Round


L15


68180-965-09


68180-965-01


68180-965-02


68180-965-03


50


White/Round


L16


68180-966-09


68180-966-01


68180-966-02


68180-966-03


75


Violet/Round


L17


68180-967-09


68180-967-01


68180-967-02


68180-967-03


88


Olive/Round


L19


68180-968-09


68180-968-01


68180-968-02


68180-968-03


100


Yellow/Round


L20


68180-969-09


68180-969-01


68180-969-02


68180-969-03


112


Rose/Round


L21


68180-970-09


68180-970-01


68180-970-02


68180-970-03


125


Tan/Round


L22


68180-971-09


68180-971-01


68180-971-02


68180-971-03


137


Turquoise/Round


L23


68180-972-09


68180-972-01


68180-972-02


68180-972-03


150


Blue/Round


L24


68180-973-09


68180-973-01


68180-973-02


68180-973-03


175


Lilac/Round


L25


68180-974-09


68180-974-01


68180-974-02


68180-974-03


200


Pink/Round


L26


68180-975-09


68180-975-01


68180-975-02


68180-975-03


300


Green/Round


L27


68180-976-09


68180-976-01


68180-976-02


68180-976-03


Storage ConditionsStore 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.

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 AdministrationInstruct patients to take levothyroxine sodium tablets only as directed by their healthcare provider.Instruct patients to take levothyroxine sodium tablets as a single dose, preferably on an empty stomach, one-half to one hour before breakfast.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.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 InformationInform patients that it may take several weeks before they notice an improvement in symptoms.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.Inform patients that levothyroxine sodium tablets should not be used as a primary or adjunctive therapy in a weight control program.Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations.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.Instruct patients to notify their physician or dentist that they are taking levothyroxine sodium tablets prior to any surgery.Adverse ReactionsInstruct 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.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 21202United StatesManufactured by:Lupin LimitedPithampur (M.P.) - 454 775INDIARevised: April 2019                                                                            ID#:260085

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