SERTRALINE HYDROCHLORIDE- sertraline hydrochloride tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - UNII:Q51BO43MG4)
Available from:
Direct_Rx
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Hypothyroidism Levothyroxine 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) Suppression Levothyroxine 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. Levothyroxine sodium tablets is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (
Product summary:
Levothyroxine Sodium Tablets, USP are supplied as follows: Strength (mcg) Color/Shape Tablet Markings NDC# for bottles of 90 NDC # for bottles of 1000 25 Orange/Caplet “25” and “GG/331” 50 White/ Caplet “50” and “GG/332” 75 Violet/ Caplet “75” and “GG/333” 88 Olive Green/ Caplet “88” and ‘GG/334” 100 Yellow/ Caplet “100” and “GG/335” 112 Rose/ Caplet “112” and “GG/336” 125 Brown/ Caplet “125” and “GG/337” 137 Turquoise/ Caplet “137” and “GG/330” 150 Blue/ Caplet “150” and “GG/338” 175 Lilac/ Caplet “175” and “GG/339” 200 Pink/ Caplet “200” and “GG/340” 300 Green/ Caplet “300” and “GG/341” Storage Conditions Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Levothyroxine sodium tablets should be protected from light and moisture.
Authorization status:
New Drug Application
Authorization number:
72189-014-90

SERTRALINE HYDROCHLORIDE- sertraline hydrochloride tablet

Direct_Rx

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SERTRALINE HYDROCHLORIDE

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)].

Hypothyroidism

Levothyroxine 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) Suppression

Levothyroxine 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

Take levothyroxine sodium tablets with a full glass of water as the tablet may rapidly disintegrate.

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 Complete

Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly

individuals who have been hypothyroid for only a short time (such as a few months). The average full

replacement dose of levothyroxine sodium tablets is approximately 1.6 mcg per kg per day (for

example: 100 to 125 mcg per day for a 70 kg adult).

Adjust the dose by 12.5 to 25 mcg increments every 4 to 6 weeks until the patient is clinically euthyroid

and the serum TSH returns to normal. Doses greater than 200 mcg per day are seldom required. An

inadequate response to daily doses of greater than 300 mcg per day is rare and may indicate poor

compliance, malabsorption, drug interactions or a combination of these factors.

For elderly patients or patients with underlying cardiac disease, start with a dose of 12.5 to 25 mcg per

day. Increase the dose every 6 to 8 weeks, as needed until the patient is clinically euthyroid and the

serum TSH returns to normal. The full replacement dose of levothyroxine sodium tablets may be less

than 1 mcg per kg per day in elderly patients.

In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg per day. Adjust

the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the patient is clinically euthyroid and the

serum TSH level is normalized.

Secondary or Tertiary Hypothyroidism

Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly

individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease

or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable

measure of levothyroxine sodium tablets dose adequacy in patients with secondary or tertiary

hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor

adequacy of therapy in this patient population. Titrate levothyroxine sodium 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 Hypothyroidism

The recommended daily dose of levothyroxine sodium tablets in pediatric patients with hypothyroidism

is based on body weight and changes with age as described in Table 1. Start levothyroxine sodium

tablets at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0-3

months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for

clinical and laboratory response [see Dosage and Administration (2.4)].

Table 1. Levothyroxine Sodium Tablets Dosing Guidelines for Pediatric Hypothyroidism

AGE Daily Dose Per Kg Body Weight a

0-3 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: 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 Cancer

Generally, 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.

Adults

In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8

weeks after any change in dose. In patients on a stable and appropriate replacement dose, evaluate

clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient’s

clinical status.

Pediatrics

In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring

both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as follows: 2 and 4

weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months

thereafter following dose stabilization until growth is completed. Poor compliance or abnormal values

may necessitate more frequent monitoring. Perform routine clinical examination, including assessment

of development, mental and physical growth and bone maturation, at regular intervals.

While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize in some

patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. Failure of the

serum T4 to increase into the upper half of the normal range within 2 weeks of initiation of

levothyroxine sodium 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 Hypothyroidism

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

Levothyroxine Sodium Tablets, USP 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”

175 mcg Lilac/ Caplet “175” and “GG/339”

200 mcg Pink/ Caplet “200” and “GG/340”

300 mcg Green/ Caplet “300” and “GG/341”

Levothyroxine sodium tablets is 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 tablets 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.

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 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.

7.1 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 2-5 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 Class Effect

Calcium 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 Class Effect

Clofibrate

Estrogen-containing oral contraceptives Estrogens (oral)

Heroin / Methadone 5-Fluorouracil

Mitotane

Tamoxifen

These drugs may increase serum thyroxine-binding globulin (TBG) concentration.

Androgens / Anabolic Steroids

Asparaginase

Glucocorticoids

Slow-Release Nicotinic Acid

These drugs may decrease serum TBG concentration.

Potential impact (below): Administration of these agents with levothyroxine sodium 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 Class Effect

Phenobarbital Rifampin Phenobarbital has been shown to reduce the response to thyroxine.

Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-

glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may

occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin

has been shown to accelerate the metabolism of levothyroxine.

Table 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 (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 tablets 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 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 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 Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including

spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth and premature delivery.

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

Dose Adjustments During Pregnancy and the Postpartum Period

Pregnancy may increase levothyroxine sodium tablets requirements. Serum TSH levels should be

monitored and the levothyroxine sodium tablets dosage adjusted during pregnancy. Since postpartum

TSH levels are similar to preconception values, the levothyroxine sodium tablets dosage should return

to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3)].

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

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 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 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

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.

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.

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:

[molecule levothyroxine sodium]

Levothyroxine sodium 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 levothyroxine sodium 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. Levothyroxine Sodium Tablets Color Additives

Strength (mcg) Color additive(s)

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 RedNo. 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)

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

12.1 Mechanism of Action

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

synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid

receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription

and synthesis of messenger RNA and cytoplasmic proteins.

The physiological actions of thyroid hormones are produced predominantly by T3, the majority of

which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

12.2 Pharmacodynamics

Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as

endogenous T4, thereby maintaining normal T4 levels when a deficiency is present.

12.3 Pharmacokinetics

Absorption

Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%. The

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

relative bioavailability of levothyroxine sodium tablets, compared to an equal nominal dose of oral

levothyroxine sodium solution, is approximately 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)].

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 t 1/2 (days) Protein Binding (%) a

Levothyroxine (T4) 10 - 20 1 6-7 b 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

13.1 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.

Levothyroxine Sodium Tablets, USP are supplied as follows:

Strength (mcg) Color/Shape Tablet Markings NDC# for bottles of 90 NDC # for bottles of 1000

25 Orange/Caplet “25” and “GG/331”

50 White/ Caplet “50” and “GG/332”

75 Violet/ Caplet “75” and “GG/333”

88 Olive Green/ Caplet “88” and ‘GG/334”

100 Yellow/ Caplet “100” and “GG/335”

112 Rose/ Caplet “112” and “GG/336”

125 Brown/ Caplet “125” and “GG/337”

137 Turquoise/ Caplet “137” and “GG/330”

150 Blue/ Caplet “150” and “GG/338”

175 Lilac/ Caplet “175” and “GG/339”

200 Pink/ Caplet “200” and “GG/340”

300 Green/ Caplet “300” and “GG/341”

Storage Conditions

Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room

Temperature]. Levothyroxine sodium tablets should be protected from light and moisture.

nform the patient of the following information to aid in the safe and effective use of levothyroxine

sodium tablets:

Dosing and Administration

Instruct patients that levothyroxine sodium tablets should be taken with a full glass of water since the

tablet may rapidly disintegrate.

Instruct 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 Information

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

Inform patients that the levothyroxine in levothyroxine sodium tablets 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 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 levothyroxine

sodium tablets therapy, but this is usually temporary.

SERTRALINE HYDROCHLORIDE

sertraline hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:7218 9 -0 14(NDC:0 78 1-518 5)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LEVO THYRO XINE SO DIUM (UNII: 9 J76 5S329 G) (LEVOTHYROXINE - UNII:Q51BO43MG4)

LEVOTHYROXINE

112 ug

Dire ct_Rx

Inactive Ingredients

Ingredient Name

Stre ng th

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

D&C RED NO . 3 0 (UNII: 2S42T28 0 8 B)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

D&C RED NO . 2 7 ALUMINUM LAKE (UNII: ZK6 4F7XSTX)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

Product Characteristics

Color

red ((ro se))

S core

2 pieces

S hap e

CAPSULE

S iz e

9 mm

Flavor

Imprint Code

112;GG;336

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:7218 9 -0 14-9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/23/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 21342

0 7/23/20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(7218 9 -0 14)

Revised: 7/2019

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