SYNTHROID (Brand for LEVOTHYROXINE SODIUM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer at least 4 hours apart from medications or food known to decrease absorption, and 4 hours apart from enteral feedings.
-Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber decrease levothyroxine absorption.
-Bioavailability is best when administered in the fasting state.
Oral Solid Formulations
Capsules:
-Administer on an empty stomach 30 to 60 minutes before breakfast.
-Do not administer capsules to patients that cannot swallow the intact capsule. The capsules should not be crushed or cut. In addition, the capsules can not be dissolved in water.
-Administer the capsule with a full glass of water to ease swallowing.

Tablets:
-Administer on an empty stomach 30 to 60 minutes before breakfast.
-Reports exist of choking, gagging, dysphagia, and tablets getting stuck in the throat. Instruct patients to take tablets with a full glass of water, as this will reduce this risk for most patients.
-Tablets may be crushed and suspended in a small amount (5 to 10 mL) of water, breast milk, or non-soy based infant formula, and administered by spoon or dropper for those unable to swallow whole tablets. Administer immediately after preparation; do not store.
-Do not mix crushed tablets with enteral feedings or soybean-based infant formulas; these reduce bioavailability.
-Tablets may be crushed and sprinkled over a small amount (5 to 10 mL) of food (e.g., cool apple sauce). Administer immediately after preparation.

Oral Liquid Formulations
Tirosint-SOL oral solution:
-Administer on an empty stomach 15 minutes before breakfast.
-May administer in water or directly into the mouth.
-To administer in water, squeeze the contents of 1 single unit-dose ampule into a glass or cup containing water and stir. Do NOT dilute with any liquid other than water.
-The preparation should be administered immediately and consumed in its entirety to ensure the entire dose is received. Rinse the glass or cup with additional water and drink the contents to ensure the entire dose is taken. Do NOT use any liquid other than water.
-To administer directly (without water), either squeeze it into the mouth or onto a spoon and immediately consume.
-Storage: Store unopened ampules in the original container (pouch) at 25 degrees C (77 degrees F ); excursions are permitted to 15 to 30 degrees C (59 to 86 degrees F). Use the oral solution within 3 months after opening the pouch.

Thyquidity oral solution:
-Administer on an empty stomach 30 to 60 minutes before breakfast.
-Administer directly into the mouth. Do NOT add to water.
-Storage: Store at 68 to 77 degrees F (20 to 25 degrees C) and dispense in original bottle. Use within 8 weeks of opening the bottle.

Extemporaneous Compounding-Oral
Extemporaneous preparation of levothyroxine 25 mcg/mL oral suspension
-With a mortar and pestle, grind twenty-five 100 mcg levothyroxine tablets into a fine powder.
-In a separate container, measure 40 mL glycerol.
-Add a small amount of the glycerol to the fine powder and mix into a uniform paste. Add geometric amounts of the glycerol until the suspension is pourable.
-Transfer suspension to a calibrated 100 mL amber bottle. In approximately 10 mL portions, rinse the mortar with the remaining glycerol and transfer washings into the amber bottle trying to leave no levothyroxine in the mortar.
-Add water to the amber bottle to bring the total volume to 100 mL.
-Label the bottle appropriately, including 'Shake well before each use' and 'Refrigerate'. The suspension is stable for 8 days when stored at 4 degrees C.

Extemporaneous preparation of levothyroxine 15 mcg/mL oral suspension
-Crush levothyroxine 100 mcg tablets in glycerol and add sterile water up to the necessary volume to create a 15 mcg/mL suspension.
-Label the bottle appropriately, including 'Shake well before each use' and 'Refrigerate'.
-The suspension is stable for 10 days when stored at 2 to 8 degrees C.
-A 12% decline in levothyroxine concentration occurred over 11 days.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Administered intravenously or intramuscularly.

Reconstitution
-Add 5 mL of preservative free NS 0.9% injection to a vial containing 100 mcg or 500 mcg to yield a concentration of 20 mcg/mL or 100 mcg/mL, respectively. Do not use other diluents. Shake well to dissolve completely.
-The solution is stable for 4 hours. Discard any unused portions.
Intravenous Administration
IV Push
-Do not add to IV infusion solutions or other IV medications; rapid degradation occurs.
-Inject over 2 to 3 minutes.

Intramuscular Administration
-Inject deeply into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel.

Monitor for signs and symptoms of hypothyroidism that could require an upward adjustment of the thyroid hormone (e.g., levothyroxine) dosage. Signs or symptoms of underdosage or hypothyroidism include constipation, cold intolerance, dry skin (xerosis) or hair, fatigue, impaired intellectual performance or other mental status changes (e.g., depression), deepening of the voice, lethargy, weight gain, tongue enlargement, and, eventually, myxedema coma.

Adverse reactions to levothyroxine are rare. Adverse reactions usually indicate inappropriate dosage of the hormone.

Transient partial alopecia may rarely occur in hypothyroid patients in the first few months of levothyroxine treatment, but normal hair growth usually recovers. Alopecia may occur during continued treatment due to hyperthyroidism from therapeutic overdosage.

In normal replacement dosages; adverse reactions to levothyroxine replacement are few; most patients tolerate therapy well and find symptomatic complaints due to hypothyroidism resolve with return to euthymia. Symptoms of adverse reactions may indicate over-replacement of the hormone. Many of the signs and symptoms of excess thyroid hormone are subtle and insidious. Manifestations of excessive dosage or hyperthyroidism include anorexia, hyperhidrosis (sweating), diarrhea, abdominal pain or cramps, dyspnea, elevated hepatic enzymes, emotional lability, fatigue, fever, flushing, headache, heat intolerance, hyperactivity, appetite stimulation/change in appetite, infertility, irritability, insomnia, menstrual irregularity (e.g., amenorrhea), muscle weakness, muscle cramps, muscle spasm, nausea, vomiting, nervousness or anxiety, tremor, and weight loss. The clinician should be alert to constellations of symptoms that gradually worsen over time. Thyrotoxicosis is rare but may result from massive overdosage producing symptoms that resemble thyroid storm, including symptoms of sympathomimetic excess. Reduce the levothyroxine dose or temporarily discontinue the hormone if signs and symptoms of overdosage appear. Treatment is primarily symptomatic and supportive. If appropriate, levothyroxine may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis function is restored in 6 to 8 weeks after cessation of therapy.

Excess levothyroxine therapy, as well as overt hyperthyroidism, can indirectly increase the workload of the heart increasing heart rate, cardiac wall thickness, and cardiac contractility; these effects may precipitate angina or arrhythmias. Excessive dosage can produce symptoms including palpitations, sinus tachycardia, atrial fibrillation, cardiac arrhythmias, hypertension, heart failure, angina, myocardial infarction, and cardiac arrest. Peripheral edema may also occur. The clinician should be alert to constellations of symptoms that gradually worsen over time. Low initial doses of levothyroxine are advised for patients where compromised integrity of the cardiovascular system, particularly the coronary arteries, is suspected or known such as patients with angina pectoris. Also, reduce the dose in such patients if an euthyroid state can only be reached at the expense of an aggravation of cardiovascular disease. During the first 2 weeks of levothyroxine for congenital hypothyroidism, monitor neonates carefully for cardiac overload, arrhythmias, and aspiration from avid suckling. All pediatric patients with cardiac disease should be carefully monitored for changes in health status during thyroid hormone therapy, particularly in the initial weeks of treatment. Young infants at increased risk for cardiac failure should receive lower initial doses. If cardiac symptoms develop or worsen, reduce the levothyroxine dose or withhold for 1 week and restart at a lower dose. Cardiac symptoms usually resolve with correction of the excessive dosage.

In infants, excessive doses of thyroid hormone preparations such as levothyroxine may produce craniosynostosis. Also, undertreatment in pediatric patients may result in slowed reduced adult height, and excessive treatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature (growth inhibition). Slipped capital femoral epiphysis has been reported in children receiving levothyroxine.

Pseudotumor cerebri (benign intracranial hypertension or increased intracranial pressure) has been reported in pediatric patients receiving thyroid hormone replacement therapy such as levothyroxine. Symptoms such as a headache, papilledema, and elevated opening pressures on lumbar puncture may occur within weeks of starting thyroid hormone replacement therapy and must be differentiated from brain metastases, if applicable.

Seizures have rarely been reported with the institution of levothyroxine therapy.

Administration of levothyroxine resulting in suppressed serum thyrotropin (TSH) concentrations has been associated with bone loss and a potential increased risk for osteopenia and the premature development of osteoporosis. The incidence and risk of the development of osteopenia in the pediatric population are unknown. Because estrogen plays a protective role against bone loss, this increased risk is thought to be particularly relevant in postmenopausal women receiving prolonged thyroid replacement therapy. In a meta-analysis conducted on pre- and postmenopausal women, data demonstrated that a greater loss of bone mass occurred in patients treated for 9.9 years with levothyroxine when compared to healthy controls.

No well-documented evidence from the literature of true allergic or idiosyncratic reactions to thyroid hormone exists. 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. Levothyroxine injection and oral dosage forms are synthetically derived and may be used in patients allergic to desiccated thyroid or thyroid extract derived from pork or beef.

Levothyroxine is contraindicated in any patient with a known hypersensitivity to levothyroxine or any of its excipients; however, there is no well-documented evidence in the literature of true allergic or idiosyncratic reactions to thyroid hormone. Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. Levothyroxine oral capsule and oral solution are contraindicated in any patient with a known (glycerol) glycerin hypersensitivity. Levothyroxine injection and tablets are synthetically derived and may be used in patients allergic to desiccated thyroid or thyroid extract derived from pork or beef.

Levothyroxine is contraindicated for use in patients with diagnosed but untreated adrenal insufficiency. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency due to an increase in the body's demand for adrenal hormones. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with levothyroxine.

Serum TSH is not a reliable measure of levothyroxine dose adequacy in patients with secondary (hypopituitarism) hypothyroidism or tertiary (hypothalamic) hypothyroidism and should not be used to monitor therapy. An inappropriate TSH may be seen if hypothyroidism is caused by TSH deficiency (e.g., secondary hypothyroidism in patients with panhypopituitarism), and the TSH will not normalize with thyroid treatment. Use the serum free-T4 level to monitor for adequacy of therapy in this patient population.

Many authorities recommend lower initial dosages and slower titration of thyroid hormones in patients with cardiac disease and coronary artery disease (CAD). Thyroid hormones such as levothyroxine should be used with great caution in patients where the integrity of the cardiovascular system is suspect. All levothyroxine dosage formulations are cardiostimulatory and should be used with great caution in patients with angina pectoris, uncontrolled hypertension, cardiac arrhythmias, CAD, a previous history of acute myocardial infarction, or current acute myocardial infarction. If adverse cardiac symptoms develop or worsen during treatment, reduce or withhold levothyroxine and cautiously restart at a lower dose. Over-treatment with thyroid hormones may cause cardiac stimulation and lead to increased heart rate, cardiac wall thickening, and increased cardiac contractility, which may precipitate angina or cardiac arrhythmias. Concomitant administration of levothyroxine with vasopressors or sympathomimetic agents may precipitate coronary insufficiency and associated symptoms, particularly in myxedematous patients or those with CAD. Fluid therapy should be administered with great care to prevent cardiac decompensation. In patients with compromised cardiac function, use thyroid hormones in conjunction with careful cardiac monitoring. A lower starting dose is recommended in pediatric patients at risk for heart failure or sensitive to thyroid stimulation. Careful monitoring is also recommended during surgery, as some anesthetic agents may induce changes in heart rate or blood pressure when administered with thyroid hormones.

Levothyroxine therapy can worsen glycemic control in patients with diabetes mellitus, and result in increased antidiabetic agent or insulin requirements. The effects seen are poorly understood and depend upon a variety of factors such as dose and type of thyroid preparations and endocrine status of the patient. Blood glucose should be monitored closely during concomitant therapy, particularly during initiation, dose adjustments, or discontinuation of therapy.

Levothyroxine should not be used for obesity treatment or weight loss. In euthyroid patients, thyroid hormone doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious manifestations of toxicity and hyperthyroidism, especially if used with anorexic agents such as the sympathomimetic amines.

Patients with myxedema coma require immediate and intensive treatment. Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism and may result in unpredictable absorption of oral thyroid hormone from the gastrointestinal tract. Initial thyroid hormone replacement for myxedema coma should be given intravenously. The use of oral thyroid hormone drug products is not recommended. Although patients with myxedema coma often suffer from hypothermia, artificial rewarming is contraindicated. Peripheral vasodilation produced by artificial external heat further decreases circulation to vital internal organs and may increase shock if present. Administration of levothyroxine may restore normal body temperature within 24 to 48 hours if heat loss is prevented by keeping the patient covered with blankets in a warm room. Patients with myxedema coma show increased sensitivity to thyroid agents; initiate therapy with low doses of intravenous levothyroxine and increase gradually. Simultaneous administration of glucocorticoids is required for these patients. Patients with pituitary myxedema should receive such adrenocortical hormone replacement therapy at or before the start of thyroid hormone treatment to prevent acute adrenocortical insufficiency and shock. Hyponatremia is frequently present in myxedema coma, but usually resolves without specific therapy as the metabolic status of the patient improves with thyroid treatment. Use great care with fluid therapy to prevent cardiac decompensation; some patients with myxedema have inappropriate secretion of ADH and are susceptible to water intoxication. In some patients, respiratory depression has been a significant factor in the development or persistence of the comatose state. Decreased oxygen saturation and elevated CO2 levels respond quickly to artificial respiration.

Long-term use of levothyroxine has been associated with decreased bone mineral density with increased bone resorption, particularly in at-risk populations (e.g., postmenopausal 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. Patients should be given the minimum dose necessary for desired clinical and biochemical response to limit risks for osteopenia.

Levothyroxine capsules (Tirosint and others) are contraindicated for use in anyone unable to swallow a capsule, generally including pediatric patients less than 6 years of age and those patients with dysphagia. Do not cut or crush the capsules. Use caution when administering the Levoxyl brand of levothyroxine tablets to patients with dysphasia or other conditions that compromise the ability to swallow. Choking, gagging, tablets getting stuck in the throat, and dysphagia have been reported, mainly when the intact tablets were not taken with water. Counsel patients to take the tablet with water.

Guidelines recommend levothyroxine (T4) as generally the preferred treatment for hypothyroidism in children, infants, and neonates. However, there are case reports of children whose TSH values could only be normalized with a combination of both T4 and T3 (liothyronine). Therefore, treatment must be individualized. Closely monitor all patients to avoid undertreatment or excessive treatment, which may produce hyperthyroidism or iatrogenic thyrotoxicosis. The management of hypothyroidism in children is similar to adults. However, there are unique differences based on the requirement of normal thyroid function for neurocognitive development as well as growth and development. There are increased weight-based requirements for thyroid hormone replacement in children and adolescents compared to adults. As the child advances through the pediatric age into adulthood thyroid hormone replacement doses decrease, with a transition to the average adult dose once endocrine maturation is complete. Careful monitoring for growth, weight, epiphyseal closure or maturation, and clinical status are important in all pediatric patients. In patients with congenital hypothyroidism, closely monitor infants during the first 2 weeks of thyroid hormone therapy for cardiac overload, arrhythmias, and aspiration from avid suckling. Undertreatment may have deleterious effects on intellectual development and linear growth. Excessive treatment 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. In children with acquired hypothyroidism, undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. 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.

Counsel patients about stopping biotin and biotin-containing supplements for at least 2 days prior to thyroid testing. Biotin in blood or other samples taken from patients who are ingesting higher biotin dosages (i.e., doses of 10 to 300 mg biotin/day) in dietary supplements, including multivitamins, prenatal vitamins, and supplements for hair, skin, and nail growth, can cause clinically significant laboratory test interference in assays that use biotin-streptavidin technology. One patient reportedly had abnormal thyroid function tests (TFTs) that did not match the clinical context after starting biotin. Within 3 days of stopping supplementation with biotin, repeated TFTs were normal. Then, biotin was reintroduced to the same patient, and TFTs taken 16 hours after the last dose and after an overnight fast showed further evidence of biotin immunoassay interference. Discuss dietary supplement intake, particularly those that may contain biotin, with patients and communicate to the lab conducting testing if the patient reports taking biotin-containing supplements. Consider laboratory test interference from biotin as a possible source of error if the lab test result does not match the clinical presentation of the patient and report any adverse events thought to be due to biotin interference to the lab test manufacturer and the FDA.

Description: Levothyroxine is an oral and parenteral synthetically prepared levorotatory isomer of thyroxine (T4), a hormone secreted by the thyroid gland that regulates multiple metabolic processes and plays an essential role in normal growth and development. Levothyroxine is used in pediatric patients as replacement therapy in the treatment of primary, secondary (pituitary), or tertiary (hypothalamic) hypothyroidism; the goal of treatment is to achieve and maintain an euthyroid state that facilitates normal physical and intellectual development and is the preferred replacement thyroid hormone in patients of all ages; other thyroid replacement hormones offer no discernable safety and efficacy advantage over levothyroxine. Thyroid replacement therapy is not used in transient hypothyroidism during the recovery phase of subacute thyroiditis. Using levothyroxine (T4) alone is sufficient in most individuals with hypothyroidism, including pediatric patients. Almost all patients receiving levothyroxine alone will become euthyroid; there are few individuals who need T3 supplementation in addition to T4 to treat symptoms or biochemical imbalance. Levothyroxine is also the preferred agent when used as a diagnostic agent in TSH suppression tests as an aid in detecting hyperthyroidism, and as an adjunct agent in the treatment of well-differentiated thyroid cancer. Intravenous levothyroxine is primarily used to treat myxedema coma, a medical emergency; oral replacement is not recommended until such patients are clinically stable. The drug may also be used for organ donor preservation during donor management. Levothyroxine has been used clinically since the 1950s; marketed products are governed by modern FDA approval processes for safety, efficacy, purity, potency, and bioequivalence. Levothyroxine has a narrow therapeutic window, as insufficient or excessive treatment may lead to undesired clinical effects; therefore, close monitoring is recommended in all patients. Levothyroxine is FDA approved for use in pediatric patients as young as neonates.

General Information
-Levothyroxine (T4) monotherapy is preferred over other forms of thyroid replacement in most patients for treatment.
-Levothyroxine is not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients.
-Levothyroxine is not indicated during the recovery phase of subacute thyroiditis.
-Dosages must be individualized based on clinical response and laboratory parameters. Peak therapeutic effect occurs in 4 to 6 weeks.-In older children, undertreatment may have deleterious effects on intellectual development and may result in poor school performance, impaired concentration, and slowed mentation. In addition, adult height may be reduced in children that are undertreated.
-Overtreatment of children with levothyroxine may result in craniosynostosis in infants, and may adversely affect the tempo of brain maturation. In addition, bone age can be accelerated leading to premature closure of the epiphyses and a reduced adult height.

-In pediatric patients, if any switch between any branded or generic levothyroxine formulations occurs, reevaluation and repeat TSH and T4 testing is recommended in 2 to 4 weeks to allow for any necessary dose titration. The FDA has classified several levothyroxine formulations as bioequivalent; consult current FDA equivalence recommendations available in the Orange Book.

For the treatment of hypothyroidism of any etiology, except during the recovery phase of subacute thyroiditis; used as a replacement in primary (thyroidal), secondary (pituitary), tertiary (hypothalamic), congenital (cretinism), or acquired hypothyroidism:
Oral dosage:
Neonates: 10 to 15 mcg/kg/dose PO once daily. May increase the dose every 4 to 6 weeks as needed. Consider lower initial doses (e.g., 25 mcg/day) in neonates with risks for cardiac failure. In neonates with very low (less than 5 mcg/dL) or undetectable serum T4, the initial starting dose is 50 mcg PO once daily.
Infants 1 to 2 months: 10 to 15 mcg/kg/dose PO once daily. May increase the dose every 4 to 6 weeks as needed. Consider lower initial doses (e.g., 25 mcg/day) in infants with risks for cardiac failure. In infants with very low (less than 5 mcg/dL) or undetectable serum T4, the initial dose is 50 mcg PO once daily.
Infants 3 to 5 months: 8 to 10 mcg/kg/dose PO once daily.
Infants 6 to 12 months: 6 to 8 mcg/kg/dose PO once daily.
Children 1 to 5 years: 5 to 6 mcg/kg/dose PO once daily. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose. May increase the dose weekly by an amount equal to 25% of the full recommended replacement dose until the recommended dose is reached.
Children 6 to 12 years: 4 to 5 mcg/kg/dose PO once daily. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose. May increase the dose weekly by an amount equal to 25% of the full recommended replacement dose until the recommended dose is reached.
Adolescents in whom growth and puberty are incomplete: 2 to 3 mcg/kg/dose PO once daily. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose. May increase the dose weekly by an amount equal to 25% of the full recommended replacement dose until the desired effect is reached.
Adolescents in whom growth and puberty are complete: 1.6 mcg/kg/dose PO once daily, initially. Adjust dose by 12.5 to 25 mcg/day every 4 to 6 weeks based on serum TSH and clinical response. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose. May increase the dose weekly by an amount equal to 25% of the full recommended replacement dose until the desired effect is reached. In severe, longstanding hypothyroidism, initiate at 12.5 to 25 mcg/day, and adjust dose by 12.5 to 25 mcg/day every 2 to 4 weeks. Doses more than 200 mcg/day are rarely required. Rare patients may require up to 300 mcg/day. Inadequate response to more than 300 mcg/day may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
Intravenous* dosage or Intramuscular* dosage:
Neonates: Initially, 5 to 8 mcg/kg/day IV or IM in patients initiating levothyroxine who are unable to take oral doses. In patients already taking an oral dose of levothyroxine who require parenteral administration, give 50% to 75% of the oral dose IV or IM once daily.
Infants, Children, and Adolescents: 50% to 75% of the previously established oral dosage given IV or IM once daily in patients who cannot take oral doses. Guidelines for hypothyroidism recommend 75% of the previously established oral dosage, assuming the enteral levothyroxine dose had achieved euthyroidism. Some patients may need titration after this initial dosage selection to maintain euthyroid status. Based on medical practice, the relative bioavailability between oral and IV administration is estimated to be 48% to 74%, and differences in absorption characteristics of patients and how they take their oral medication necessitate the use of TSH measurements a few weeks after initiating therapy to ensure proper dose adjustments.

For use as hormonal replacement therapy for organ preservation* in brain dead donors prior to procurement:
Intravenous dosage:
Neonates and Infants < 6 months: 5 mcg/kg/dose IV bolus, then 1.4 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Infants 6 to 12 months: 4 mcg/kg/dose IV bolus, then 1.3 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Children 1 to 5 years: 3 mcg/kg/dose IV bolus, then 1.2 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Children 6 to 11 years: 2.5 mcg/kg/dose IV bolus, then 1 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Children and Adolescents 12 to 16 years: 1.5 mcg/kg/dose IV bolus, then 0.8 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Adolescents > 16 years: 0.8 mcg/kg/dose IV bolus, then 0.8 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.

Therapeutic Drug Monitoring:
General Recommendations
-Thyroid function tests to aid in assessing response to thyroid hormone therapy. Age appropriate references for normal values should be used. Frequently used tests include:
--thyroid stimulating hormone (TSH)
-total serum thyroxine (T4)
-free thyroxine (unbound T4).

-Factors that influence the laboratory results of thyroid function tests must be monitored. These include, but are not limited to, drugs, acute and chronic disease states, age, endogenous proteins, etc. Complete clinical evaluation to monitor improvement in signs and symptoms of hypothyroidism and hyperthyroidism is required. Inadequate response to higher than usual maximum doses may indicate poor compliance, malabsorption, or drug interactions.
-In patients with secondary and tertiary hypothyroidism, serum TSH is not a reliable measure of dose adequacy and should not be used; monitor serum free-T4 levels and titrate until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.
-In pediatric patients, failure of T4 to increase into the upper half of the normal range within 2 weeks of levothyroxine initiation or failure of TSH to decrease below 20 milliunits/L within 4 weeks should prompt therapy evaluation, with consideration given to patient compliance and concomitant medical conditions or medications.
--In neonates, caution is necessary in interpreting results of thyroid function tests since serum T4 concentrations are transiently elevated and T3 concentrations are transiently low. Also, the immature pituitary gland is relatively insensitive to the negative feedback effect of thyroid hormones, and therefore TSH may not normalize.
-During the first 2 weeks of therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration from avid suckling.


Frequency of Monitoring
-Monitor the serum TSH and the total or free T4. During the first 3 years of life, the serum total or free T4 should be maintained in the upper half of the normal range.-In the first year of life, monitoring should occur 2 and 4 weeks after drug initiation, then every 1 to 2 months. After 1 year of age, monitoring can occur every 2 to 3 months until the child is 3 years of age. Guidelines from the American Academy of Pediatrics, the American Thyroid Association, and the Lawson Wilkins Pediatric Endocrine Society suggest that after 6 months of age, monitoring every 3 to 4 months until the child is 3 years of age is adequate.
-In children over 3 years of age, monitor every 3 to 12 months until growth is completed. Others suggest that monitoring every 6 to 12 months is adequate in children over 3 years of age with stable thyroid function.

-If there is a change in the dosage of levothyroxine, the manufacturer recommends that a TSH and T4 concentration be monitored 2 weeks after the change. Others recommend a free T4 and TSH concentrations be obtained 4 weeks after a dose change.

Maximum Dosage Limits:
There is no maximum dose. Levothyroxine is a narrow therapeutic index drug that requires monitoring; dosage must be individualized.

Patients with Hepatic Impairment Dosing
No specific dosage adjustments are needed; dosing is individualized to achieve therapeutic goals.

Patients with Renal Impairment Dosing
Levothyroxine is known to be substantially excreted by the kidney, and the risk of toxic reactions may be increased in patients with renal impairment. Care should be used during initial dose selection. Dosing is individualized to achieve therapeutic goals.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Levothyroxine exhibits all the actions of endogenous thyroid hormone. Liothyronine (T3) is the principal hormone that exhibits these actions whereas levothyroxine (T4) is the major hormone secreted by the thyroid gland and is metabolically deiodinated to T3 in peripheral tissues. Approximately 80% of a levothyroxine dose is deiodinated to T3 and reverse T3, and virtually all of the activity of levothyroxine can be ascribed to the conversion of the drug to T3. Serum concentrations of T4 and TSH are typically used as the primary monitoring parameters for determining thyroid function.

In general, thyroid hormones influence the growth and maturation of tissues, increase energy expenditure, and affect the turnover of essentially all substrates. These effects are mediated through control of DNA transcription and, ultimately, protein synthesis. Thyroid hormones play an integral role in both anabolic and catabolic processes and are particularly important to the development of the central nervous system in newborns. They regulate cell differentiation and proliferation and aid in the myelination of nerves and the development of axonal and dendritic processes in the nervous system. Thyroid hormones, along with somatotropin, are responsible for regulating growth, particularly of bones and teeth. Thyroid hormones also decrease cholesterol concentrations in the liver and the bloodstream and have a direct cardiostimulatory action. Cardiac consumption is increased by the administration of thyroid hormone, resulting in increased cardiac output. Administration of exogenous thyroid hormone to patients with hypothyroidism increases the metabolic rate by enhancing protein and carbohydrate metabolism, increasing gluconeogenesis, facilitating the mobilization of glycogen stores, and increasing protein synthesis. In response to reestablishing physiologic levels of thyroid hormone, thyroid-stimulating hormone (TSH) concentrations correct if the primary disorder is at the level of the thyroid.

The release of endogenous T3 and T4 from the thyroid gland into the systemic circulation is regulated by TSH (thyrotropin, also known as thyroid stimulating hormone), which is secreted by the anterior pituitary gland. Thyrotropin release is controlled by the secretion of thyroid-releasing hormone (TRH) from the hypothalamus and by a feedback mechanism dependent on the concentrations of circulating thyroid hormones. When circulating T3 and T4 levels increase, the activities of TRH and TSH decrease. Because of this feedback mechanism, the administration of pharmacologic doses of exogenous thyroid hormone to patients with a normal thyroid suppresses endogenous thyroid hormone secretion.

Pharmacokinetics: Levothyroxine is administered orally or intravenously. Over 99% of levothyroxine (T4) is bound to proteins, primarily thyroxine-binding globulin (TGB), prealbumin, and albumin. These proteins have a higher affinity for T4 than for liothyronine (T3). Many medications and concurrent clinical conditions may affect T4 protein-binding, resulting in clinically significant changes in thyroid hormone activity since free (unbound) drug is metabolically active. Thyroid hormones do not readily cross the placental barrier, and only minimal amounts are distributed into breast milk.
Levothyroxine (T4) exhibits a slow metabolic clearance. 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. 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 feces. Urinary excretion of T4 decreases with age. The elimination half-life of levothyroxine is 6 to 7 days in euthyroid patients, 9 to 10 days in hypothyroid patients, and 3 to 4 days in hyperthyroid patients. The elimination half-life of T3 is 2 days or less. Levothyroxine has a slower onset of action and a longer duration than liothyronine. Full therapeutic effects of levothyroxine may not be evident for 1 to 3 weeks following oral administration and persist for the same amount of time following cessation of therapy. As the hypothyroid patient becomes euthyroid, TSH secretion decreases.

Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: uridine 5'-diphospho-glucuronosyltransferase (UGT), and possibly intestinal P-glycoprotein (P-gp)
The induction of uridine 5'-diphospho-glucuronosyltransferase (UGT) by other medications increases L-thyroxine hepatic metabolism and leads to a lower T4 serum levels. The literature has reported that levothyroxine might inhibit P-gp, and lower cyclosporine concentrations; however, this action of levothyroxine requires further study.


-Route-Specific Pharmacokinetics
Oral Route
Absorption of orally administered levothyroxine (T4) from the gastrointestinal tract ranges from 40% to 80%. Based on medical practice, the relative bioavailability of oral levothyroxine is 48 to 74% that of the injectable levothyroxine sodium. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of the oral tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption. Certain foods, like soybean infant formula, enteral feedings, and dietary fiber, decrease T4 absorption.

Consistent tablet potency was an issue with oral levothyroxine products prior to 1984. In 1984, the USP required all manufacturers to use HPLC to monitor levothyroxine tablet content to ensure tablet potency. With the new manufacturing and testing processes, oral levothyroxine product potency issues have not been a significant problem.

Intravenous Route
Following intravenous (IV) administration, the synthetic levothyroxine is 100% available and cannot be distinguished from the natural hormone that is secreted endogenously. Levothyroxine injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients. Intravenous levothyroxine treatment in severely hypothyroid patients may lead to improvement in cardiovascular, renal, pulmonary, and metabolic parameters within a week. Serum thyroxine and triiodothyronine concentrations may improve or normalize with a similar time frame, with more gradual improvement in serum TSH.