HIGHLIGHTS OF PRESCRIBING INFORMATION --------------------------------CONTRAINDICATIONS----------------------------­

• Uncorrected adrenal insufficiency. (4)

These highlights do not include all the information needed to use
LEVO-T® safely and effectively. See full prescribing information for ------------------------WARNINGS AND PRECAUTIONS-----------------­
LEVO-T. • Cardiac adverse reactions in the elderly and in patients with underlying
cardiovascular disease: Initiate LEVO-T at less than the full
LEVO-T® (levothyroxine sodium) tablets, for oral use replacement dose because of the increased risk of cardiac adverse
Initial U.S. Approval: 2002 reactions, including atrial fibrillation. (2.3, 5.1, 8.5)
• Myxedema coma: Do not use oral thyroid hormone drug products to treat
myxedema coma. (5.2)
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR
• Acute adrenal crisis in patients with concomitant adrenal insufficiency:
WEIGHT LOSS
Treat with replacement glucocorticoids prior to initiation of LEVO-T
See full prescribing information for complete boxed warning treatment. (5.3)
• Thyroid hormones, including Levo-T should not be used for the • Prevention of hyperthyroidism or incomplete treatment of
treatment of obesity or for weight loss. hypothyroidism: Proper dose titration and careful monitoring is critical
• Doses beyond the range of daily hormonal requirements may to prevent the persistence of hypothyroidism or the development of
produce serious or even life threatening manifestations of toxicity (6, hyperthyroidism. (5.4)
10). • Worsening of diabetic control: Therapy in patients with diabetes
mellitus may worsen glycemic control and result in increased
----------------------------INDICATIONS AND USAGE--------------------------­ antidiabetic agent or insulin requirements. Carefully monitor glycemic
LEVO-T is L-thyroxine (T4) indicated for: control after starting, changing, or discontinuing thyroid hormone
• Hypothyroidism: As replacement therapy in primary (thyroidal), therapy. (5.5)
secondary (pituitary), and tertiary (hypothalamic) congenital or acquired • Decreased bone mineral density associated with thyroid hormone over-
hypothyroidism. (1) replacement: Over-replacement can increase bone resorption and
• Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) decrease bone mineral density. Give the lowest effective dose. (5.6)
Suppression: As an adjunct to surgery and radioiodine therapy in the
management of thyrotropin-dependent well-differentiated thyroid --------------------------------ADVERSE REACTIONS----------------------------­
cancer. (1) Adverse reactions associated with LEVO-T therapy are primarily those of
Limitations of Use: hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial
- Not indicated for suppression of benign thyroid nodules and nontoxic infarction, dyspnea, muscle spasm, headache, nervousness, irritability,
diffuse goiter in iodine-sufficient patients. insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea,
- Not indicated for treatment of hypothyroidism during the recovery heat intolerance, menstrual irregularities, and skin rash. (6)
phase of subacute thyroiditis.
To report SUSPECTED ADVERSE REACTIONS, contact Neolpharma,
-----------------------DOSAGE AND ADMINISTRATION----------------------­ Inc. at 1-844-200-4163 or FDA at 1-800-FDA-1088 or
• Administer once daily, preferably on an empty stomach, one-half to one www.fda.gov/medwatch.
hour before breakfast. (2.1)
• Administer at least 4 hours before or after drugs that are known to ---------------------------------DRUG INTERACTIONS---------------------------­
interfere with absorption. (2.1) See full prescribing information for drugs that affect thyroid hormone
pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion,
• Evaluate the need for dose adjustments when regularly administering
catabolism, protein binding, and target tissue response) and may alter the
within one hour of certain foods that may affect absorption. (2.1)
therapeutic response to LEVO-T. (7)
• Starting dose depends on a variety of factors, including age, body
weight, cardiovascular status, and concomitant medications. Peak
-------------------------USE IN SPECIFIC POPULATIONS---------------------­
therapeutic effect may not be attained for 4-6 weeks. (2.2)
Pregnancy may require the use of higher doses of LEVO-T. (2.3, 8.1)
• See full prescribing information for dosing in specific patient
populations. (2.3)
• Adequacy of therapy determined with periodic monitoring of TSH See 17 for PATIENT COUNSELING INFORMATION.
and/or T4 as well as clinical status. (2.4)

-----------------------DOSAGE FORMS AND STRENGTHS-------------------­ Revised: 12/2017

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

Reference ID: 4190666

 FULL PRESCRIBING INFORMATION: CONTENTS*
7.5 Antidepressant Therapy
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR 7.6 Ketamine
WEIGHT LOSS 7.7 Sympathomimetics
1 INDICATIONS AND USAGE 7.8 Tyrosine-Kinase Inhibitors
2 DOSAGE AND ADMINISTRATION 7.9 Drug-Food Interactions
2.1 General Administration Information 7.10 Drug-Laboratory Test Interactions
2.2 General Principles of Dosing 8 USE IN SPECIFIC POPULATIONS
2.3 Dosing in Specific Patient Populations 8.1 Pregnancy
2.4 Monitoring TSH and/or Thyroxine (T4) Levels 8.2 Lactation
3 DOSAGE FORMS AND STRENGTHS 8.4 Pediatric Use
4 CONTRAINDICATIONS 8.5 Geriatric Use
5 WARNINGS AND PRECAUTIONS 10 OVERDOSAGE
5.1 Cardiac Adverse Reactions in the Elderly and in Patients
11 DESCRIPTION
with Underlying Cardiovascular Disease
12 CLINICAL PHARMACOLOGY
5.2 Myxedema Coma 12.1 Mechanism of Action
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal
12.2 Pharmacodynamics
Insufficiency
12.3 Pharmacokinetics
5.4 Prevention of Hyperthyroidism or Incomplete Treatment
13 NONCLINICAL TOXICOLOGY
of Hypothyroidism
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.5 Worsening of Diabetic Control 16 HOW SUPPLIED/STORAGE AND HANDLING
5.6 Decreased Bone Mineral Density Associated with Thyroid
17 PATIENT COUNSELING INFORMATION
Hormone Over-Replacement

6 ADVERSE REACTIONS
7 DRUG INTERACTIONS *Sections or subsections omitted from the full prescribing information
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics are not listed.
7.2 Antidiabetic Therapy
7.3 Oral Anticoagulants
7.4 Digitalis Glycosides

Reference ID: 4190666

 FULL PRESCRIBING INFORMATION

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including Levo-T, 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

Hypothyroidism
LEVO-T is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and
tertiary (hypothalamic) congenital or acquired hypothyroidism.

Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

LEVO-T is indicated as an adjunct to surgery and radioiodine therapy in the management of
thyrotropin-dependent well-differentiated thyroid cancer.

Limitations of Use:
• LEVO-T is not indicated for suppression of benign thyroid nodules and nontoxic
diffuse goiter in iodine-sufficient patients as there are no clinical benefits and
overtreatment with LEVO-T may induce hyperthyroidism [see Warnings and
Precautions (5.4)].

• LEVO-T is not indicated for treatment of hypothyroidism during the recovery phase of
subacute thyroiditis.

2 DOSAGE AND ADMINISTRATION

2.1 General Administration Information

Take LEVO-T with a full glass of water as the tablet may rapidly disintegrate.

Administer LEVO-T as a single daily dose, on an empty stomach, one-half to one hour before
breakfast.

Administer LEVO-T at least 4 hours before or after drugs known to interfere with LEVO-T
absorption [see Drug Interactions (7.1)].

Evaluate the need for dose adjustments when regularly administering within one hour of certain
foods that may affect LEVO-T absorption [see Drug Interactions (7.9) and Clinical
Pharmacology (12.3)].

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 Administer LEVO-T 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 LEVO-T, such as soybean-
based infant formula [see Drug Interactions (7.9)].

2.2 General Principles of Dosing

The dose of LEVO-T 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 LEVO-T may not be attained for 4 to 6 weeks.

2.3 Dosing in Specific Patient Populations

Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are
Complete
Start LEVO-T 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 LEVO-T 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 LEVO-T may be
less than 1 mcg per kg per day in elderly patients.

In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg per day.
Adjust the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the patient is clinically
euthyroid and the serum TSH level is normalized.

Secondary or Tertiary Hypothyroidism

Start LEVO-T 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 LEVO-T 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 LEVO-T 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.
Reference ID: 4190666
 Pediatric Dosage - Congenital or Acquired Hypothyroidism
The recommended daily dose of LEVO-T in pediatric patients with hypothyroidism is based on
body weight and changes with age as described in Table 1. Start LEVO-T at the full daily dose
in most pediatric patients. Start at a lower starting dose in newborns (0-3 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. LEVO-T Dosing Guidelines for Pediatric Hypothyroidism

AGE Daily Dose Per Kg Body Weighta
0-3 months 10-15 mcg/kg/day
3-6 months 8-10 mcg/kg/day
6-12 months 6-8 mcg/kg/day
1-5 years 5-6 mcg/kg/day
6-12 years 4-5 mcg/kg/day
Greater than 12 years but growth and puberty incomplete 2-3 mcg/kg/day
Growth and puberty complete 1.6 mcg/kg/day
a. The dose should be adjusted based on clinical response and laboratory parameters [see Dosage and
Administration (2.4) and Use in Specific Populations (8.4)].

Newborns (0-3 months) at risk for cardiac failure: Consider a lower starting dose in newborns at
risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and
laboratory response.

Children at risk for hyperactivity: To minimize the risk of hyperactivity in children, start at one-
fourth the recommended full replacement dose, and increase on a weekly basis by one-fourth the
full recommended replacement dose until the full recommended replacement dose is reached.

Pregnancy
Pre-existing Hypothyroidism: LEVO-T 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 LEVO-T by 12.5 to 25 mcg/day and measure TSH every 4
weeks until a stable LEVO-T dose is reached and serum TSH is within the normal trimester-
specific range. Reduce LEVO-T dosage to pre-pregnancy levels immediately after delivery and
measure serum TSH levels 4 to 8 weeks postpartum to ensure LEVO-T 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 LEVO-T 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 LEVO-T at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4
weeks and adjust LEVO-T dosage until a serum TSH is within the normal trimester specific
range [see Use in Specific Populations (8.1)].

TSH Suppression in Well-differentiated Thyroid Cancer

Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a LEVO-T dose
of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level

Reference ID: 4190666

 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 LEVO-T may be evidence of inadequate absorption, poor
compliance, drug interactions, or a combination of these factors.

Adults
In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6
to 8 weeks after any change in dose. In patients on a stable and appropriate replacement dose,
evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change
in the patient’s clinical status.

Pediatrics
In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by
measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children
as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage,
and then every 3 to 12 months thereafter following dose stabilization until growth is
completed. Poor compliance or abnormal values may necessitate more frequent monitoring.
Perform routine clinical examination, including assessment of development, mental and
physical growth, and bone maturation, at regular intervals.

While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize
in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid
feedback. Failure of the serum T4 to increase into the upper half of the normal range within 2
weeks of initiation of LEVO-T 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 LEVO-T [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.

3 DOSAGE FORMS AND STRENGTHS

LEVO-T tablets are available as follows:

Tablet Strength Tablet Color/Shape Tablet Markings

25 mcg Orange/Caplet “25” and “GG/331”
50 mcg White/ Caplet “50” and “GG/332”
75 mcg Violet/ Caplet “75” and “GG/333”
88 mcg Olive Green/ Caplet “88” and “GG/334”
100 mcg Yellow/ Caplet “100” and “GG/335”
112 mcg Rose/ Caplet “112” and “GG/336”
125 mcg Brown/ Caplet “125” and “GG/337”
137 mcg Turquoise/ Caplet “137” and “GG/330”
150 mcg Blue/ Caplet “150” and “GG/338”

Reference ID: 4190666

 175 mcg Lilac/ Caplet “175” and “GG/339”
200 mcg Pink/ Caplet “200” and “GG/340”
300 mcg Green/ Caplet “300” and “GG/341”

4 CONTRAINDICATIONS

LEVO-T is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and
Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

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 LEVO-T 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 LEVO-T therapy. Monitor patients receiving concomitant LEVO­
T and sympathomimetic agents for signs and symptoms of coronary insufficiency.

If cardiac symptoms develop or worsen, reduce the LEVO-T 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 LEVO-T [see Contraindications (4)].

5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism

LEVO-T has a narrow therapeutic index. Over- or undertreatment with LEVO-T 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 LEVO-T 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 LEVO-T and adjust the dose as necessary [see Drug Interactions
(7.9) and Clinical Pharmacology (12.3)].

5.5 Worsening of Diabetic Control

Reference ID: 4190666
 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 LEVO-T [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 LEVO-T that achieves the desired clinical and
biochemical response to mitigate this risk.

6 ADVERSE REACTIONS

Adverse reactions associated with LEVO-T 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 Children

Pseudotumor 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 Reactions
Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid
hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various
gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia,
serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

7 DRUG INTERACTIONS

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

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 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 LEVO-T (see Tables 2-5 below).

Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)

Potential impact: Concurrent use may reduce the efficacy of LEVO-T by binding and
delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class Effect
Calcium Carbonate Calcium carbonate may form an insoluble chelate with
Ferrous Sulfate levothyroxine, and ferrous sulfate likely forms a ferric-
thyroxine complex. Administer LEVO-T at least 4 hours
apart from these agents.
Orlistat Monitor patients treated concomitantly with orlistat and
LEVO-T for changes in thyroid function.
Bile Acid Sequestrants Bile acid sequestrants and ion exchange resins are known to
-Colesevelam decrease levothyroxine absorption. Administer LEVO-T at
-Cholestyramine least 4 hours prior to these drugs or monitor TSH levels.
-Colestipol
Ion Exchange Resins
-Kayexalate
-Sevelamer
Other drugs: Gastric acidity is an essential requirement for adequate
Proton Pump Inhibitors absorption of levothyroxine. Sucralfate, antacids and proton
Sucralfate pump inhibitors may cause hypochlorhydria, affect intragastric
Antacids pH, and reduce levothyroxine absorption. Monitor patients
- Aluminum & Magnesium appropriately.
Hydroxides
- Simethicone

Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without
Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class Effect
Clofibrate These drugs may increase serum thyroxine-binding globulin
Estrogen-containing oral (TBG) concentration.
contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids These drugs may decrease serum TBG concentration.
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Potential impact (below): Administration of these agents with LEVO-T results in an initial
transient increase in FT4. Continued administration results in a decrease in serum T4 and normal
FT4 and TSH concentrations.

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 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: These drugs may cause protein-binding site displacement.
Carbamazepine Furosemide has been shown to inhibit the protein binding of
Furosemide (> 80 mg IV) T4 to TBG and albumin, causing an increase free T4 fraction
Heparin in serum. Furosemide competes for T4-binding sites on TBG,
Hydantoins prealbumin, and albumin, so that a single high dose can
Non-Steroidal Anti-inflammatory acutely lower the total T4 level. Phenytoin and carbamazepine
Drugs reduce serum protein binding of levothyroxine, and total and
-Fenamates 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 LEVO-T
requirements.
Drug or Drug Class Effect
Phenobarbital Phenobarbital has been shown to reduce the response to
Rifampin 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 T3

Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion
of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but
may occasionally be slightly increased.
Drug or Drug Class Effect
Beta-adrenergic antagonists In patients treated with large doses of propranolol (> 160
(e.g., Propranolol > 160 mg/day) 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 Short-term administration of large doses of glucocorticoids
(e.g., Dexamethasone > 4 may decrease serum T3 concentrations by 30% with minimal
mg/day) 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 inhibits peripheral conversion of levothyroxine
Amiodarone (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.

Reference ID: 4190666

 7.2 Antidiabetic Therapy
Addition of LEVO-T 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

LEVO-T 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 LEVO-T
dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage
adjustments.

7.4 Digitalis Glycosides

LEVO-T 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 LEVO-T 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. LEVO-T may accelerate the onset
of action of tricyclics. Administration of sertraline in patients stabilized on LEVO-T may result
in increased LEVO-T requirements.

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

7.7 Sympathomimetics
Concurrent use of sympathomimetics and LEVO-T 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 LEVO-T 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 LEVO-T from the gastrointestinal tract.
Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

7.10 Drug-Laboratory Test Interactions

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 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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Risk Summary

Experience with levothyroxine use in pregnant women, including data from post-marketing
studies, have not reported increased rates of major birth defects or miscarriages [see Data].
There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy.
Since TSH levels may increase during pregnancy, TSH should be monitored and LEVO-T
dosage adjusted during pregnancy [see Clinical Considerations]. There are no animal studies
conducted with levothyroxine during pregnancy. LEVO-T should not be discontinued during
pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

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

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

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

Dose Adjustments During Pregnancy and the Postpartum Period

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

Data

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

8.2 Lactation
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 Risk Summary

Limited published studies report that levothyroxine is present in human milk. However, there is
insufficient information to determine the effects of Levothyroxine on the breastfed infant and no
available information on the effects of levothyroxine on milk production. Adequate
levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating
mothers. The developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for LEVO-T and any potential adverse effects on the breastfed
infant from LEVO-T or from the underlying maternal condition.

8.4 Pediatric Use

The initial dose of LEVO-T 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 LEVO-T 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 LEVO-T therapy immediately upon diagnosis.
Levothyroxine is generally continued for life in these patients.

Closely monitor infants during the first 2 weeks of LEVO-T 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 Patients

Closely 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 LEVO­
T 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

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 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 LEVO-T 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

LEVO-T (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 C15H10I4NNaO4•xH2O (where x = 5), molecular weight of 798.86 g/mol (anhydrous),
and structural formula as shown:

LEVO-T tablets for oral administration are supplied in the following strengths: 25 mcg, 50
mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, and
300 mcg. Each LEVO-T tablet contains the inactive ingredients Magnesium Stearate, NF;
Microcrystalline Cellulose, NF; Colloidal Silicone Dioxide, NF; and Sodium Starch
Glycolate, NF. Each tablet strength meets USP Dissolution Test 2. Table 6 provides a listing
of the color additives by tablet strength:

Table 6. LEVO-T Tablets Color Additives

Strength Color additive(s)
(mcg)
25 FD&C Yellow No. 6 Aluminum Lake
50 None
75 FD&C Blue No. 2 Aluminum Lake, D&C Red No. 27 Aluminum Lake
88 FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, D&C
Red No. 30 Aluminum Lake
100 D&C Yellow No. 10 Aluminum Lake, D&C Red Lake Blend (D&C Red No. 27
Lake and D&C Red No. 30 Lake)

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 112 D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake
125 FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake,
FD&C Blue No. 1 Aluminum Lake
137 FD&C Blue No. 1 Aluminum Lake
150 FD&C Blue No. 2 Aluminum Lake
175 D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake, FD&C Blue
No. 1 Aluminum Lake
200 D&C Yellow No. 10 Aluminum Lake, D&C Red No. 27 Aluminum Lake
300 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake,
FD&C Blue No. 1 Aluminum Lake

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 LEVO-T dose is absorbed from the jejunum and upper ileum. The relative
bioavailability of LEVO-T tablets, compared to an equal nominal dose of oral levothyroxine
sodium solution, is approximately 99%. 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)].

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 Elimination
Metabolism
T4 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.

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 7. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone Ratio in Thyroglobulin Biologic Potency t1/2 (days) Protein Binding (%)a
Levothyroxine (T4) 10 - 20 1 6-7b 99.96
Liothyronine (T3) 1 4 ≤2 99.5
a. Includes TBG, TBPA, and TBA
b. 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism

13 NONCLINICAL TOXICOLOGY

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

LEVO-T (levothyroxine sodium, USP) tablets are supplied as follows:

Strength Color/Shape Tablet Markings NDC# for NDC # for
(mcg) bottles of 90 bottles of 1000
25 Orange/Caplet “25” and “GG/331” 55466-104-11 55466-104-19

50 White/ Caplet “50” and “GG/332” 55466-105-11 55466-105-19

75 Violet/ Caplet “75” and “GG/333” 55466-106-11 55466-106-19

88 Olive Green/ Caplet “88” and ‘GG/334” 55466-107-11 -­

100 Yellow/ Caplet “100” and “GG/335” 55466-108-11 55466-108-19

112 Rose/ Caplet “112” and “GG/336” 55466-109-11 -­

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 125 Brown/ Caplet “125” and “GG/337” 55466-110-11 55466-110-19

137 Turquoise/ Caplet “137” and “GG/330” 55466-111-11 -­

150 Blue/ Caplet “150” and “GG/338” 55466-112-11 -­

175 Lilac/ Caplet “175” and “GG/339” 55466-113-11 -­

200 Pink/ Caplet “200” and “GG/340” 55466-114-11 -­

300 Green/ Caplet “300” and “GG/341” 55466-115-11 -­

Storage Conditions
Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled
Room Temperature]. LEVO-T tablets 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
LEVO-T:

Dosing and Administration

• Instruct patients that LEVO-T should be taken with a full glass of water since the tablet may
rapidly disintegrate.
• Instruct patients to take LEVO-T only as directed by their healthcare provider.
• Instruct patients to take LEVO-T 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 LEVO-T 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 LEVO-T.

Important Information

• Inform patients that it may take several weeks before they notice an improvement in
symptoms.
• Inform patients that the levothyroxine in LEVO-T 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 LEVO-T 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,
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 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 LEVO-T. 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 LEVO-T prior to any
surgery.

Adverse Reactions

• 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.
• Inform patients that partial hair loss may occur rarely during the first few months of LEVO-T
therapy, but this is usually temporary.

Manufactured and Distributed by:

Neolpharma, Inc.

Caguas, Puerto Rico 00725

December 2017

PP10402

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