LEVOTIRON

Levothyroxine is a synthetically produced form of thyroxine, a major endogenous hormone secreted by the thyroid gland.

Also known as L-thyroxine or the brand name product Synthroid, levothyroxine is used primarily to treat hypothyroidism, a condition where the thyroid gland is no longer able to produce sufficient quantities of the thyroid hormones T 4 (tetraiodothyronine or thyroxine) and T 3 (triiodothyronine or Liothyronine ), resulting in diminished down-stream effects of these hormones.

Without sufficient quantities of circulating thyroid hormones, symptoms of hypothyroidism begin to develop such as fatigue, increased heart rate, depression 4, dry skin and hair, muscle cramps, constipation, weight gain, memory impairment, and poor tolerance to cold temperatures. 16, 10 In response to Thyroid Stimulating Hormone (TSH) release by the pituitary gland, a normally functioning thyroid gland will produce and secrete T 4, which is then converted through deiodination (by type I or type II 5′-deiodinases) 8 into its active metabolite T 3.

T is the major product secreted by the thyroid gland, T 3 exerts the majority of the physiological effects of the thyroid hormones; T and T 3 have a relative potency of ~1:4 (T4:T3).

T and

T 3 act on nearly every cell of the body, but have a particularly strong effect on the cardiac system.

As a result, many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status.

Prior to the development of levothyroxine, Thyroid, porcine or desiccated thyroid, used to be the mainstay of treatment for hypothyroidism.

However, this is no longer recommended for the majority of patients due to several clinical concerns including limited controlled trials supporting its use.

Desiccated thyroid products contain a ratio of T4 to T3 of 4.2:1, which is significantly lower than the 14:1 ratio of secretion by the human thyroid gland.

This higher proportion of

T3 in desiccated thyroid products can lead to supraphysiologic levels of T3 which may put patients at risk of thyrotoxicosis if thyroid extract therapy is not adjusted according to the serum TSH. 10, 16.

Levothyroxine is indicated as replacement therapy in primary (thyroidal), secondary (pituitary) and tertiary (hypothalamic) congenital or acquired hypothyroidism.

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

Oral levothyroxine is a synthetic hormone that exerts the same physiologic effect as endogenous T 4, thereby maintaining normal T 4 levels when a deficiency is present.

Levothyroxine has a narrow therapeutic index and is titrated to maintain a euthyroid state with TSH (thyroid stimulating hormone) within a therapeutic range of 0.4–4.0 mIU/L.

• or under-treatment with levothyroxine 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.

The dose of levothyroxine should be titrated slowly and carefully and patients should be monitored for their response to titration to avoid these effects.

TSH levels should be monitored at least yearly to avoid over-treating with levothyroxine which can result in hyperthyroidism (TSH <0.1mIU/L) and symptoms of increased heart rate, diarrhea, tremor, hypercalcemia, and weakness to name a few.

As many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status, 7 over-treatment with levothyroxine may result in increases 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.

In populations with any cardiac concerns, levothyroxine should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease.

Patients receiving concomitant levothyroxine and sympathomimetic agents should be monitored for signs and symptoms of coronary insufficiency.

If cardiac symptoms develop or worsen, reduce the levothyroxine dose or withhold for one week and restart at a lower dose.

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

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.

Integrin alpha-V Binder

Integrin beta-3 Binder Thyroid hormone receptor alpha Agonist + 1 more target.

of Oral administered T4 from the gastrointestinal tract ranges from 40% to 80% with the majority of the levothyroxine dose absorbed from the jejunum and upper ileum.

T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans, milk, and dietary fiber.

Absorption may also decrease with age.

In addition, many drugs affect T4 absorption including bile acide sequestrants, sucralfate, proton pump inhibitors, and minerals such as calcium (including in yogurt and milk products) 3, magnesium, iron, and aluminum supplements.

To prevent the formation of insoluble chelates, levothyroxine should generally be taken on an empty stomach at least 2 hours before a meal and separated by at least 4 hours from any interacting agents.

Approximately 70% of secreted T is deiodinated to equal amounts of T and reverse triiodothyronine (rT 3 ), which is calorigenically inactive.

T is slowly eliminated through its major metabolic pathway to T 3 via sequential deiodination, where approximately 80% of circulating T is derived from peripheral T 4.

The liver is the major site of degradation for both T and T 3, with T 4 deiodination also occurring at a number of additional sites, including the kidney and other tissues.

Elimination of T and

T 3 involves hepatic conjugation to glucuronic and sulfuric acids.

The hormones undergo enterohepatic circulation as conjugates are hydrolyzed in the intestine and reabsorbed.

Conjugated compounds that reach the colon are hydrolyzed and eliminated as free compounds in the feces.

Other minor

T 4 metabolites have been identified.

Hover over products below to view reaction partners Levothyroxine Liothyronine Reverse triiodothyronine (rT3) Diiodothyronine.

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 T is eliminated in the stool.

Urinary excretion of

T 4 decreases with age.

T 4 half-life is 6-7 days.

T 3 half-life is 1-2 days.

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=20 mg/kg (Oral in rat).

Hypermetabolic state indistinguishable from thyrotoxicosis of endogenous origin.

Symptoms of thyrotoxicosis include weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, tremors, insomnia, heat intolerance, fever, and menstrual irregularities.

Levothyroxine sodium tablets are contraindicated in patients with uncorrected adrenal insufficiency.

Uncorrected adrenal insufficiency.

Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast with a full glass of water.

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

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

Advise patients to stop biotin and biotin-containing supplements at least 2 days before assessing TSH and/or T4 levels.

Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, and concomitant medications.

Peak therapeutic effect may not be attained for to 6 weeks.

See full prescribing information for dosing in specific patient populations.

Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status. 2.1 Important Administration Instructions Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half to one hour before breakfast with a full glass of water to avoid choking or gagging.

Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere with levothyroxine sodium absorption.

Evaluate the need for dosage adjustments when regularly administering within one hour of certain foods that may affect levothyroxine sodium tablets absorption.

Administer levothyroxine sodium tablets to pediatric patients who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL) of water and immediately administering the suspension by spoon or dropper.

Ensure the patient ingests the full amount of the suspension.

Do not store the suspension.

Do not administer in foods that decrease absorption of levothyroxine sodium tablets, such as soybean-based infant formula. 2.2 Important Considerations for Dosing The dosage of levothyroxine sodium tablets for hypothyroidism or pituitary TSH suppression depends on a variety of factors including: the patient's age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food and the specific nature of the condition being treated.

Dosing must be individualized to account for these factors and dosage adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters.

For adult patients with primary hypothyroidism, titrate until the patient is clinically euthyroid and the serum TSH returns to normal.

For secondary or tertiary hypothyroidism, serum TSH is not a reliable measure of levothyroxine sodium dosage adequacy and should not be used to monitor therapy.

Use the serum free-T4 level to titrate levothyroxine sodium tablets dosing until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

Inquire whether patients are taking biotin or biotin-containing supplements.

If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels.

The peak therapeutic effect of a given dose of levothyroxine sodium tablets may not be attained for to 6 weeks. 2.3 Recommended Dosage and Titration Primary, Secondary, and Tertiary Hypothyroidism in Adults The recommended starting daily dosage of levothyroxine sodium tablets in adults with primary, secondary, or tertiary hypothyroidism is based on age and comorbid cardiac conditions, as described in Table 1.

For patients at risk of atrial fibrillation or patients with underlying cardiac disease, start with a lower dosage and titrate the dosage more slowly to avoid exacerbation of cardiac symptoms.

Dosage titration is based on serum

TSH or free-T4.

Table 1.

Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Adults Dosages greater than 200 mcg/day are seldom required.

An inadequate response to daily dosages greater than 300 mcg/day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.

Patient Population Starting Dosage Dosage Titration Based on serum TSH or Free-T4 Adults diagnosed with hypothyroidism Full replacement dose is 1.6 mcg/kg/day. Some patients require a lower starting dose.

Titrate dosage by 12.5 to 25 mcg increments every to 6 weeks, as needed until the patient is euthyroid.

Adults at risk for atrial fibrillation or with underlying cardiac disease Lower starting dose (less than 1.6 mcg/kg/day) Titrate dosage every to 8 weeks, as needed until the patient is euthyroid.

Geriatric patients

Lower starting dose (less than 1.6 mcg/kg/day) Primary, Secondary, and Tertiary Hypothyroidism in Pediatric Patients The recommended starting daily dosage of levothyroxine sodium tablets in pediatric patients with primary, secondary, or tertiary hypothyroidism is based on body weight and changes with age as described in Table 2.

Titrate the dosage (every 2 weeks) as needed based on serum TSH or free-T4 until the patient is euthyroid.

Table 2.

Levothyroxine Sodium Tablets Dosing Guidelines for Hypothyroidism in Pediatric Patients Age Starting Daily Dosage Per Kg Body Weight 0 to 3 months to 15 mcg/kg/day to 6 months to 10 mcg/kg/day to 12 months to 8 mcg/kg/day to 5 years to 6 mcg/kg/day to 12 years to 5 mcg/kg/day Greater than 12 years but growth and puberty incomplete to 3 mcg/kg/day Growth and puberty complete 1.6 mcg/kg/day Adjust dosage based on clinical response and laboratory parameters.

Pediatric Patients from

Birth to 3 Months of Age at Risk for Cardiac Failure Start at a lower starting dosage and increase the dosage every to 6 weeks as needed based on clinical and laboratory response.

To minimize the risk of hyperactivity, start at one-fourth the recommended full replacement dosage, and increase on a weekly basis by one-fourth the full recommended replacement dosage until the full recommended replacement dosage is reached.

For pregnant patients with pre-existing hypothyroidism, measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy.

In pregnant patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range.

The recommended daily dosage of levothyroxine sodium tablets in pregnant patients is described in Table 3.

Table 3.

Levothyroxine Sodium Tablet Dosing Guidelines for Hypothyroidism in Pregnant Patients Patient Population Starting Dosage Dose Adjustment and Titration Pre-existing primary hypothyroidism with serum TSH above normal trimester.

• specific range Pre-pregnancy dosage may increase during pregnancy Increase levothyroxine sodium dosage by 12.5 to 25 mcg per day. Monitor TSH every 4 weeks until a stable dose is reached and serum TSH is within normal trimester-specific range.

Reduce levothyroxine sodium dosage to pre-pregnancy levels immediately after delivery.

Monitor serum

TSH to 8 weeks postpartum.

New onset hypothyroidism (TSH ≥10 mIU per liter) 1.6 mcg/kg/day Monitor serum TSH every 4 weeks and adjust levothyroxine sodium dosage until serum TSH is within normal trimester-specific range.

New onset hypothyroidism (TSH < 10 mIU per liter) 1.0 mcg/kg/day TSH Suppression in Well-differentiated Thyroid Cancer in Adult and Pediatric Patients The levothyroxine sodium dosage is based on the target level of TSH suppression for the stage and clinical status of thyroid cancer. 2.4 Monitoring TSH and/or Thyroxine (T4) Levels Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation.

Biotin supplementation may interfere with immunoassays for TSH, T4, and T3, resulting in erroneous thyroid hormone test results.

Stop biotin and biotin-containing supplements for at least 2 days before assessing TSH and/or T4 levels.

Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of levothyroxine sodium may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors.

In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of to 8 weeks after any change in dosage.

In patients on a stable and appropriate replacement dosage, evaluate clinical and biochemical response every to 12 months and whenever there is a change in the patient’s clinical status.

In patients with hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4.

TSH and total or free-T4 in pediatric patients as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every to 12 months thereafter following dosage stabilization until growth is completed.

Poor compliance or abnormal values may necessitate more frequent monitoring.

Perform routine clinical examination, including assessment of development, mental and physical growth, and bone maturation, at regular intervals.

The general aim of therapy is to normalize the serum TSH level.

TSH may not normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback.

Failure of the serum

T4 to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium therapy and/or of the serum TSH to decrease below 20 mIU per litre within 4 weeks may indicate the patient is not receiving adequate therapy.

Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of levothyroxine sodium.

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

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The clinical experience, including data from postmarketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy.

TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine sodium dosage adjusted during pregnancy.

Animal reproductive studies have not been conducted with levothyroxine sodium.

Levothyroxine sodium should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

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

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 requirements.

TSH levels should be monitored and the levothyroxine sodium dosage adjusted during pregnancy.

Since postpartum

TSH levels are similar to preconception values, the levothyroxine sodium dosage should return to the pre-pregnancy dose immediately after delivery.

Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine.

No adverse effects on the breastfed infant have been reported and there is no information on the effects of levothyroxine on milk production.

Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levothyroxine sodium and any potential adverse effects on the breastfed infant from levothyroxine sodium or from the underlying maternal condition.

Levothyroxine sodium is indicated in patients from birth to less than 17 years of age: As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Rapid restoration of normal serum

T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation.

Therefore, initiate levothyroxine sodium therapy immediately upon diagnosis.

Levothyroxine is generally continued for life in these patients.

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

Because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium at less than the full replacement dose.

Atrial arrhythmias can occur in elderly patients.

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