FDA Label for Euthyrox

Warning: Not For Treatment Of Obesity Or For Weight Loss

• Thyroid hormones, including EUTHYROX, 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)].

Other

Hypothyroidism

EUTHYROX is indicated in pediatric and adult patients as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

EUTHYROX is indicated in pediatric and adult patients as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Limitations of Use:

• EUTHYROX 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 EUTHYROX may induce hyperthyroidism [see Warnings and Precautions (5.4)].
• EUTHYROX is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty Are Complete

Start EUTHYROX 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 EUTHYROX is approximately 1.6 mcg per kg per day (for example: 100 mcg per day to 125 mcg per day for a 70 kg adult).

Adjust the dose by 12.5 mcg 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 mcg per day 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 EUTHYROX 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 mcg per day to 25 mcg per day. Adjust the dose in 12.5 mcg 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 EUTHYROX 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 EUTHYROX dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 (L-thyroxine) level to monitor adequacy of therapy in this patient population. Titrate EUTHYROX 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 EUTHYROX in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start EUTHYROX at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0 to 3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response [see Dosage and Administration (2.4)].

Table 1. EUTHROX Dosing Guidelines for Pediatric Hypothyroidism

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

Newborns (0 to 3 months) at Risk for Cardiac Failure:

Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response.

Pediatric Patients at Risk for Hyperactivity:

To minimize the risk of hyperactivity in pediatric patients, 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: EUTHYROX dose requirements may increase during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at a 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 EUTHYROX by 12.5 mcg daily to 25 mcg daily and measure TSH every 4 weeks until a stable EUTHYROX dose is reached and serum TSH is within the normal trimester-specific range. Reduce EUTHYROX dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure EUTHYROX 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 EUTHYROX at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH less than 10 mIU per liter) start EUTHYROX at 1 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust EUTHYROX 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

The dose of EUTHYROX should target TSH levels within the desired therapeutic range. This may require a EUTHYROX dose of greater than 2 mcg per kg per day, depending on the target level for TSH suppression.

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 EUTHYROX therapy and/or of the serum TSH to decrease below 20 mIU 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 EUTHYROX [see Warnings and Precautions (5.4) 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.

Adverse Reactions in Pediatric Patients

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in pediatric patients 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.

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 thyroid-stimulating hormone (TSH) levels may increase during pregnancy, TSH should be monitored and EUTHYROX dosage adjusted during pregnancy (see Clinical Considerations). There are no animal studies conducted with levothyroxine during pregnancy. EUTHYROX 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 Postpartum Period

Pregnancy may increase EUTHYROX requirements. Serum TSH level should be monitored and the EUTHYROX dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the EUTHYROX 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.

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 EUTHYROX and any potential adverse effects on the breastfed infant from EUTHYROX or from the underlying maternal condition.

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 EUTHYROX therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients.

Closely monitor infants during the first 2 weeks of EUTHYROX 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 has been associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and accelerate the bone age, with resultant premature closure of the epiphyses 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.

Absorption

Absorption of orally administered T₄ from the gastrointestinal tract ranges from 40% to 80%. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of EUTHYROX 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 thyroxine-binding 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 (Table 6). 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.

Table 6: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone	Ratio in Thyroglobulin	Biologic Potency	t½ (days)	Protein Binding (%) Includes TBG, TBPA, and TBA
Levothyroxine (T4)	10–20	1	6–7 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism	99.96
Liothyronine (T3)	1	4	≤ 2	99.5

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.

Dosing and Administration

• Instruct patients to take EUTHYROX only as directed by their healthcare provider.
• Instruct patients to take EUTHYROX 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 EUTHYROX 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 EUTHYROX.

Important Information

• Inform patients that it may take several weeks before they notice an improvement in symptoms.
• Inform patients that the levothyroxine in EUTHYROX 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 EUTHYROX 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 EUTHYROX. 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 EUTHYROX 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 EUTHYROX therapy, but this is usually temporary.

Rx Only

Manufactured by:
Merck KGaA
Frankfurter Straße 250
64293 Darmstadt, Germany

Marketed by:
Provell Pharmaceuticals, LLC
1801 Horseshoe Pike – Suite 1
Honey Brook, PA 19344 US

Revised: 09/2018

2.1 General Administration Information

Administer EUTHYROX tablets orally as a single daily dose, on an empty stomach, one-half to one hour before breakfast.

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

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

Administer EUTHYROX to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 mL to 10 mL or 1 teaspoon 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 EUTHYROX, such as soybean-based infant formula [see Drug Interactions (7.9)].

2.2 General Principles Of Dosing

The dose of EUTHYROX 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), 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 EUTHYROX may not be attained for 4 to 6 weeks.

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

3 Dosage Forms And Strengths

EUTHYROX tablets are uncoated, off-white, round and flat on both sides with a beveled edge, and a dividing score on both sides available as:

4 Contraindications

EUTHYROX 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

Overtreatment 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 EUTHYROX 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 EUTHYROX therapy. Monitor patients receiving concomitant EUTHYROX and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiovascular symptoms develop or worsen, reduce or withhold the EUTHYROX dose 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 EUTHYROX [see Contraindications (4)].

5.4 Prevention Of Hyperthyroidism Or Incomplete Treatment Of Hypothyroidism

EUTHYROX has a narrow therapeutic index. Over- or under-treatment with EUTHYROX may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Titrate the dose of EUTHYROX 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 EUTHYROX and adjust the dose as necessary [see Drug Interactions (7), 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 EUTHYROX [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 EUTHYROX that achieves the desired clinical and biochemical response to mitigate against this risk.

6 Adverse Reactions

Adverse reactions associated with EUTHYROX 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, muscular weakness and cramps
• Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest
• Respiratory: dyspnea
• Gastrointestinal: diarrhea, vomiting, abdominal cramps and 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 levothyroxine therapy.

7.1 Drugs Known To Affect Thyroid Hormone Pharmacokinetics

Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to EUTHYROX (see Tables 2 – 5).

7.2 Antidiabetic Therapy

Addition of EUTHYROX 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 EUTHYROX is started, changed, or discontinued [see Warnings and Precautions (5.5)].

7.3 Oral Anticoagulants

EUTHYROX 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 EUTHYROX dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

7.4 Digitalis Glycosides

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

7.6 Ketamine

Concurrent use of ketamine and EUTHYROX may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

7.7 Sympathomimetics

Concurrent use of sympathomimetics and EUTHYROX 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 EUTHYROX absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1)]. Soybean flour (infant formula), cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of EUTHYROX 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 concentrations. 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.

8.4 Pediatric Use

The initial dose of EUTHYROX 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 EUTHYROX 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.

8.5 Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, initiate EUTHYROX at less than the full replacement dose [see Warnings and Precautions (5.1) and Dosage and Administration (2.3)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

10 Overdosage

The signs and symptoms of overdosage are those of hyperthyroidism [See Warnings and Precautions (5.4) 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 levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

Reduce the EUTHYROX 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

EUTHYROX contains the active ingredient, levothyroxine, a synthetic crystalline levothyroxine (T₄) in sodium salt form. It is chemically designated as L-3,3',5,5'-tetraiodothyronine monosodium hydrate. Synthetic T₄ is identical in chemical structure to the T₄ produced in the human thyroid gland. Levothyroxine sodium has the molecular formula C₁₅H₁₀I₄NNaO₄ ∙ xH₂O, molecular weight of 798.85 (anhydrous), and structural formula as shown:

Chemical Structure - euthyrox 01

EUTHYROX 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, and 200 mcg. Inactive ingredients citric acid anhydrous, corn starch, gelatin, magnesium stearate, mannitol, sodium croscarmellose.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

EUTHYROX (levothyroxine sodium) tablets are uncoated, off-white, round and flat on both sides with a beveled edge, and a dividing score on both sides available as:

Each carton contains 30 tablets with 2 blister packs. Each blister pack contains 15 tablets placed in individual cavities.

Storage And Handling

Store between 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light and moisture, avoid heat. Do not separate the individual cavities containing the tablet from the intact blister and do not remove the individual tablets from blister packaging until ready to use.

17 Patient Counseling Information

Inform the patient of the following information to aid in the safe and effective use of EUTHYROX:

Principal Display Panel - 25 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
25 mcg per tablet, USP

Rx only

NDC 72305-025-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 50 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
50 mcg per tablet, USP

Rx only

NDC 72305-050-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 75 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
75 mcg per tablet, USP

Rx only

NDC 72305-075-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 88 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
88 mcg per tablet, USP

Rx only

NDC 72305-088-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 100 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
100 mcg per tablet, USP

Rx only

NDC 72305-100-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 112 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
112 mcg per tablet, USP

Rx only

NDC 72305-112-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 125 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
125 mcg per tablet, USP

Rx only

NDC 72305-125-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 137 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
137 mcg per tablet, USP

Rx only

NDC 72305-137-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 150 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
150 mcg per tablet, USP

Rx only

NDC 72305-150-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 175 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
175 mcg per tablet, USP

Rx only

NDC 72305-175-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC

Principal Display Panel - 200 Mcg Tablet Blister Pack Carton

Euthyrox^®
(levothyroxine sodium) tablets
200 mcg per tablet, USP

Rx only

NDC 72305-200-30

Do not remove individual tablets from
blister packaging until ready to use.

30 Tablets (2 x 15 tablets per blister pack)

PROVELL
PHARMACEUTICALS LLC