As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.
Pituitary TSH Suppression
In the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.
Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin-stimulating hormone, TSH, from the anterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, L-thyroxine (T4) and L-triiodothyronine (T3), by the thyroid gland. Circulating serum T3 and T4 levels exert a feedback effect on both TRH and TSH secretion. When serum T3 and T4 levels increase, TRH and TSH secretion decrease. When thyroid hormone levels decrease, TRH and TSH secretion increase.
The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T3 and 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.
Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development.
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.
Levothyroxine, at doses individualized according to patient response, is effective as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.
Levothyroxine is also effective in the suppression of pituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimoto’s thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer
Patients should be informed of the following information to aid in the safe and effective use of levothyroxine sodium:
|1. Notify your physician if you are allergic to any foods or medicines, are pregnant or intend to become pregnant, are breast-feeding or are taking any other medications, including prescription and over-the-counter preparations.|
|2. Notify your physician of any other medical conditions you may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems. Your dose of medications used to control these other conditions may need to be adjusted while you are taking levothyroxine sodium. If you have diabetes, monitor your blood and/or urinary glucose levels as directed by your physician and immediately report any changes to your physician. If you are taking anticoagulants (blood thinners), your clotting status should be checked frequently.|
|3. Use levothyroxine sodium only as prescribed by your physician. Do not discontinue or change the amount you take or how often you take it, unless directed to do so by your physician.|
|4. The levothyroxine in levothyroxine sodium tablets is intended to replace a hormone that is normally produced by your thyroid gland. Generally, replacement therapy is to be taken for life, except in cases of transient hypothyroidism, which is usually associated with an inflammation of the thyroid gland (thyroiditis).|
|5. Take levothyroxine sodium in the morning on an empty stomach, at least one-half hour before eating any food.|
|6. It may take several weeks before you notice an improvement in your symptoms.|
|7. Notify your physician if you 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.|
|8. Notify your physician if you become pregnant while taking levothyroxine sodium. It is likely that your dose of levothyroxine sodium will need to be increased while you are pregnant.|
|9. Notify your physician or dentist that you are taking levothyroxine sodium prior to any surgery.
10. Partial hair loss may occur rarely during the first few months of levothyroxine sodium therapy, but this is usually temporary.
|11. Levothyroxine sodium should not be used as a primary or adjunctive therapy in a weight control program. 12. Keep levothyroxine sodium tablets out of the reach of children. Store levothyroxine sodium tablets away from heat, moisture, and light.|
The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation assay sensitivity ≤ 0.1 mIU/L or third generation assay sensitivity ≤ 0.01 mIU/L) and measurement of free-T4.
The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. The choice of laboratory tests depends on various factors including the etiology of the underlying thyroid disease, the presence of concomitant medical conditions, including pregnancy, and the use of concomitant medications (see PRECAUTIONS: Drug Interactions and Drug-Laboratory Test Interactions). 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 decreased T4 potency of the drug product.
In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6 to 8 week intervals until normalization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after 8 to 12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6 to 12 months, depending on the clinical situation, and whenever there is a change in the patient’s status. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving levothyroxine sodium.
In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring both serum TSH (using a sensitive assay) and total- or free-T4. During the first three years of life, the serum total- or free-T4 should be maintained at all times in the upper half of the normal range. While the aim of therapy is to also normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid feedback threshold as a result of in utero hypothyroidism. 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 mU/L within 4 weeks should alert the physician to the possibility that the child is not receiving adequate therapy. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of levothyroxine sodium.
The recommended frequency of monitoring of TSH and total or free T4 in children is as follows: at 2 and 4 weeks after the initiation of treatment; every 1 to 2 months during the first year of life; every 2 to 3 months between 1 and 3 years of age; and every 3 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T4 levels, and a physical examination, if indicated, be performed 2 weeks after any change in levothyroxine sodium dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals.
Secondary (Pituitary) and Tertiary (Hypothalamic) Hypothyroidism
Adequacy of therapy should be assessed by measuring serum free-T4 levels, which should be maintained in the upper half of the normal range in these patients.
Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage. They include the following:
General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating;
Central Nervous System: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia;
Musculoskeletal: tremors, muscle weakness;
Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest;
Gastrointestinal: diarrhea, vomiting, abdominal cramps and elevations in liver function tests;
Dermatologic: hair loss, flushing;
Endocrine: decreased bone mineral density;
Reproductive: menstrual irregularities, impaired fertility.
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.
Seizures have been reported rarely with the institution of levothyroxine therapy.
Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism.
Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.
Onset of action: Therapeutic: Oral: 3-5 days; I.V. 6-8 hours
Peak effect: I.V.: ~24 hours
Absorption: Oral: Erratic (40% to 80%); decreases with age
Protein binding: >99%
Metabolism: Hepatic to triiodothyronine (active)
Time to peak, serum: 2-4 hours
Half-life elimination: Euthyroid: 6-7 days; Hypothyroid: 9-10 days; Hyperthyroid: 3-4 days
Doses should be adjusted based on clinical response and laboratory parameters.
Newborns: Initial: 10-15 mcg/kg/day. Lower doses of 25 mcg/day should be considered in newborns at risk for cardiac failure. Newborns with T4 levels <5 mcg/dL should be started at 50 mcg/day. Adjust dose at 4- to 6-week intervals.
Infants and Children: Dose based on body weight and age as listed below. Children with severe or chronic hypothyroidism should be started at 25 mcg/day; adjust dose by 25 mcg every 2-4 weeks. In older children, hyperactivity may be decreased by starting with 1/4 of the recommended dose and increasing by 1/4 dose each week until the full replacement dose is reached. Refer to adult dosing once growth and puberty are complete.
|0-3 months: 10-15 mcg/kg/day
3-6 months: 8-10 mcg/kg/day
6-12 months: 6-8 mcg/kg/day
1-5 years: 5-6 mcg/kg/day
6-12 years: 4-5 mcg/kg/day
>12 years: 2-3 mcg/kg/day
Hypothyroidism: 1.7 mcg/kg/day in otherwise healthy adults <50 years old, children in whom growth and puberty are complete,
and older adults who have been recently treated for hyperthyroidism or who have been hypothyroid for only a few months.
Titrate dose every 6 weeks. Average starting dose ~100 mcg; usual doses are </=200 mcg/day; doses >/=300 mcg/day are rare
(consider poor compliance, malabsorption, and/or drug interactions). Note: For patients >50 years or patients with cardiac
disease, refer to Elderly dosing.
Severe hypothyroidism: Initial: 12.5-25 mcg/day; adjust dose by 25 mcg/day every 2-4 weeks as appropriate; Note: Oral agents are not recommended for myxedema (see I.V. dosing).
Subclinical hypothyroidism (if treated): 1 mcg/kg/day
Well-differentiated thyroid cancer: Highly individualized; Doses >2 mcg/kg/day may be needed to suppress TSH to <0.1 mU/L.
Benign nodules and nontoxic multinodular goiter: Goal TSH suppression: 0.1-0.3 mU/L
>50 years without cardiac disease or <50 years with cardiac disease: Initial: 25-50 mcg/day; adjust dose at 6- to 8-week
intervals as needed
>50 years with cardiac disease: Initial: 12.5-25 mcg/day; adjust dose by 12.5-25 mcg increments at 4- to 6-week intervals
Note: Elderly patients may require <1 mcg/kg/day
Children, Adults, Elderly: Hypothyroidism: 50% of the oral dose
Adults: Myxedema coma or stupor: 200-500 mcg, then 100-300 mcg the next day if necessary; smaller doses should be considered in patients with cardiovascular disease.
Elderly: Myxedema coma: Refer to Adults dosing; lower doses may be needed
Oral: Administer in the morning on an empty stomach, at least 30 minutes before food. Tablets may be crushed and suspended in 1-2 teaspoonfuls of water; suspension should be used immediately.
Parenteral: Dilute vial with 5 mL normal saline; use immediately after reconstitution; should not be admixed with other solutions
Thyroid function test (serum thyroxine, thyrotropin concentrations), resin triiodothyronine uptake (rT3U), free thyroxine index (FTI), T4, TSH, heart rate, blood pressure, clinical signs of hypo- and hyperthyroidism; TSH is the most reliable guide for evaluating adequacy of thyroid replacement dosage. TSH may be elevated during the first few months of thyroid replacement despite patients being clinically euthyroid. In cases where T4 remains low and TSH is within normal limits, an evaluation of “free” (unbound) T4 is needed to evaluate further increase in dosage
Infants: Monitor closely for cardiac overload, arrhythmias, and aspiration from avid suckling
Infants/children: Monitor closely for under/overtreatment. Undertreatment may decrease intellectual development and linear growth, and lead to poor school performance due to impaired concentration and slowed mentation. Overtreatment may adversely affect brain maturation, accelerate bone age (leading to premature closure of the epiphyses and reduced adult height); craniosynostosis has been reported in infants. Treated children may experience a period of catch-up growth. Monitor TSH and
total or free T4 at 2 and 4 weeks after starting treatment; every 1-2 months for first year of life; every 2-3 months during years 1-3; every 3-12 months until growth completed.
Adults: Monitor TSH every 6-8 weeks until normalized; 8-12 weeks after dosage changes; every 6-12 months throughout therapy
Cord T4 and values in the first few weeks are much higher, falling over the first months and years.
>/=10 years: ~5.8-11 mcg/dL (SI: 75-142 nmol/L).
Borderline low: </= 4.5-5.7 mcg/dL (SI: 58-73 nmol/L);
low: </=4.4 mcg/dL (SI: 57 nmol/L);
results <2.5 mcg/dL (SI: <32 nmol/L) are strong evidence for hypothyroidism.
Approximate adult normal range:
4-12 mcg/dL (SI: 51-154 nmol/L).
Borderline high: 11.1-13 mcg/dL (SI: 143-167 nmol/L);
high: >/=13.1 mcg/dL (SI: 169 nmol/L).
Normal range is increased in women on birth control pills (5.5-12 mcg/dL);
normal range in pregnancy: ~5.5-16 mcg/dL (SI: ~71-206 nmol/L).
TSH: 0.4-10 (for those >/=80 years) mIU/L;
T4: 4-12 mcg/dL (SI: 51-154 nmol/L);
T3 (RIA) (total T3): 80-230 ng/dL (SI: 1.2-3.5 nmol/L);
T4 free (free T4): 0.7-1.8 ng/dL (SI: 9-23 pmol/L).
Approximate equivalencies – Monitor closely if switching from one product to another.
-Levothyroxine sodium (T4) 100 mcg
-Thyroid (desiccated) 60-65 mg
-Liothyronine sodium (T3) 25 mcg
-Liotrix® 12.5 mcg T3/50 mcg T4
Injection, powder for reconstitution, as sodium: 0.2 mg, 0.5 mg
Tablet, as sodium: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 150 mcg, 175 mcg, 200 mcg, 300 mcg
Levothroid®: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg [DSC], 150 mcg, 175 mcg, 200 mcg, 300 mcg
Levoxyl®, Synthroid®: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, 300 mcg
Unithroid®: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 150 mcg, 175 mcg, 200 mcg, 300 mcg
National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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