Levothyroxine

Pronunciation

(lee voe thye ROKS een)


U.S. Brand Names

Levothroid®; Levoxyl®; Synthroid®; Unithroid®



Synonyms

Levothyroxine Sodium; -Thyroxine Sodium; T4

L

Generic Available

Yes



Canadian Brand Names

Eltroxin®; Synthroid®



Use

Replacement or supplemental therapy in hypothyroidism; pituitary TSH suppression



Pregnancy Risk Factor

A



Pregnancy Implications

Untreated maternal hypothyroidism may have adverse effects on fetal growth and development and is associated with higher rate of complications (spontaneous abortion, pre-eclampsia, stillbirth, premature delivery). Treatment should not be discontinued during pregnancy. TSH levels should be monitored during each trimester and 6-8 weeks postpartum. Increased doses may be needed during pregnancy.



Lactation

Enters breast milk/compatible



Contraindications

Hypersensitivity to levothyroxine sodium or any component of the formulation; recent MI or thyrotoxicosis; uncorrected adrenal insufficiency



Warnings/Precautions

Ineffective and potentially toxic for weight reduction; high doses may produce serious or even life-threatening toxic effects particularly when used with some anorectic drugs. Use with caution and reduce dosage in patients with angina pectoris or other cardiovascular disease; use cautiously in elderly since they may be more likely to have compromised cardiovascular functions. Patients with adrenal insufficiency, myxedema, diabetes mellitus and insipidus may have symptoms exaggerated or aggravated; thyroid replacement requires periodic assessment of thyroid status. Chronic hypothyroidism predisposes patients to coronary artery disease.



Adverse Reactions

Frequency not defined.

Cardiovascular: Angina, arrhythmia, blood pressure increased, cardiac arrest, flushing, heart failure, MI, palpitation, pulse increased, tachycardia

Central nervous system: Anxiety, emotional lability, fatigue, fever, headache, hyperactivity, insomnia, irritability, nervousness, pseudotumor cerebri (children), seizure (rare)

Dermatologic: Alopecia

Endocrine & metabolic: Fertility impaired, menstrual irregularities

Gastrointestinal: Abdominal cramps, appetite increased, diarrhea, vomiting, weight loss

Hepatic: Liver function tests increased

Neuromuscular & skeletal: Bone mineral density decreased, muscle weakness, tremor, slipped capital femoral epiphysis (children)

Respiratory: Dyspnea

Miscellaneous: Diaphoresis, heat intolerance, hypersensitivity (to inactive ingredients, symptoms include urticaria, pruritus, rash, flushing, angioedema, GI symptoms, fever, arthralgia, serum sickness, wheezing)

Overdosage/Toxicology

Chronic: Chronic overdose may cause hyperthyroidism, weight loss, nervousness, sweating, tachycardia, insomnia, heat intolerance, menstrual irregularities, palpitations, psychosis, and fever. Overtreatment of children may result in premature closure of epiphyses or craniosynostosis (infants). Reduce dose or temporarily discontinue therapy. Hypothalamic-pituitary-thyroid axis will return to normal in 6-8 weeks. Serum T4 levels do not correlate well with toxicity. Provide general supportive care

Acute: Acute overdose may cause fever, hypoglycemia, CHF, and unrecognized adrenal insufficiency. Acute massive overdose may be life-threatening; treatment should be symptomatic and supportive. Massive overdose may be a require beta-blockers for increased sympathomimetic activity.

Drug Interactions

Also refer to Additional Information.

Aluminum- and magnesium-containing antacids, calcium carbonate, simethicone, or sucralfate: May decrease T4 absorption; separate dose from levothyroxine by at least 4 hours.

Antidiabetic agents (biguanides, meglitinides, sulfonylureas, thiazolidinediones, insulin): Changes in thyroid function may alter requirements of antidiabetic agent. Monitor closely at initiation of therapy, or when dose is changed or discontinued.

Cholestyramine and colestipol: Decrease T4 absorption; separate dose from levothyroxine by at least 2 hours.

Digoxin: Digoxin levels may be reduced in hyperthyroidism; therapeutic effect may be reduced. Impact of thyroid replacement should be monitored.

Estrogens: May decrease serum free thyroxine concentrations.

Iron: Decreases T4 absorption; separate dose from levothyroxine by at least 4 hours.

Kayexalate®: Decreases T4 absorption; separate dose from levothyroxine by at least 4 hours.

Ketamine: May cause marked hypertension and tachycardia; monitor.

Theophylline, caffeine: Decreased theophylline clearance in hypothyroid patients; monitor during thyroid replacement.

Tricyclic and tetracyclic antidepressants: Therapeutic and toxic effects of levothyroxine and the antidepressant are increased.

Warfarin (and other oral anticoagulants): The hypoprothrombinemic response to warfarin may be altered by a change in thyroid function or replacement. Replacement may dramatically increase response to warfarin. However, initiation of warfarin in a patient stabilized on a dose of levothyroxine does not appear to require a significantly different approach.

Ethanol/Nutrition/Herb Interactions

Food: Taking levothyroxine with enteral nutrition may cause reduced bioavailability and may lower serum thyroxine levels leading to signs or symptoms of hypothyroidism. Limit intake of goitrogenic foods (eg, asparagus, cabbage, peas, turnip greens, broccoli, spinach, Brussels sprouts, lettuce, soybeans). Soybean flour (infant formula), cottonseed meal, walnuts, and dietary fiber may decrease absorption of levothyroxine from the GI tract.



Stability

Tablet: Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Injection: Store at room temperature of 15°C to 30°C (59°F to 86°F). Dilute vials for injection with 5 mL normal saline and shake well; reconstituted solutions should be used immediately and any unused portions discarded. Do not mix I.V. solution with other I.V. infusion solutions.

Compatibility

Do not mix I.V. solution with other I.V. infusion solutions.



Mechanism of Action

Exact mechanism of action is unknown; however, it is believed the thyroid hormone exerts its many metabolic effects through control of DNA transcription and protein synthesis; involved in normal metabolism, growth, and development; promotes gluconeogenesis, increases utilization and mobilization of glycogen stores, and stimulates protein synthesis, increases basal metabolic rate



Pharmacodynamics/Kinetics

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

Excretion: Urine and feces; decreases with age

Dosage

Doses should be adjusted based on clinical response and laboratory parameters.

Oral:

Children: Hypothyroidism:

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

Adults:

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

TSH suppression:

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

Elderly: Hypothyroidism:

>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

I.M., I.V.: Children, Adults, Elderly: Hypothyroidism: 50% of the oral dose

I.V.:

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

Administration

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

Monitoring Parameters

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

Reference Range

Pediatrics: 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).

Test Interactions

Many drugs may have effects on thyroid function tests (see Additional Information). Pregnancy, infectious hepatitis, and acute intermittent porphyria may increase TBG concentrations; nephrosis, severe hypoproteinemia, severe liver disease, and acromegaly may decrease TBG concentrations.



Dietary Considerations

Should be taken on an empty stomach, at least 30 minutes before food.



Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Thyroid replacement therapy is generally for life. Take as directed, in the morning before breakfast. Do not take antacids or iron preparations within 8 hours of thyroid medication. Do not change brands and do not discontinue without consulting prescriber. Consult prescriber if drastically increasing or decreasing intake of goitrogenic food (eg, asparagus, cabbage, peas, turnip greens, broccoli, spinach, Brussels sprouts, lettuce, soybeans). Report chest pain, rapid heart rate, palpitations, heat intolerance, excessive sweating, increased nervousness, agitation, or lethargy.



Additional Information

Equivalent doses: Thyroid USP 60 mg ~ levothyroxine 0.05-0.06 mg ~ liothyronine 0.015-0.0375 mg

50-60 mg thyroid ~ 50-60 mcg levothyroxine and 12.5-15 mcg liothyronine Liotrix®

Note: Several medications have effects on thyroid production or conversion. The impact in thyroid replacement has not been specifically evaluated, but patient response should be monitored:

Methimazole: Decreases thyroid hormone secretion, while propylthiouracil decrease thyroid hormone secretion and decreases conversion of T4 to T3.

Beta-adrenergic antagonists: Decrease conversion of T4 to T3 (dose related, propranolol

160 mg/day); patients may be clinically euthyroid.

Iodide, iodine-containing radiographic contrast agents may decrease thyroid hormone secretion; may also increase thyroid hormone secretion, especially in patients with Graves' disease.

Other agents reported to impact on thyroid production/conversion include aminoglutethimide, amiodarone, chloral hydrate, diazepam, ethionamide, interferon-alpha, interleukin-2, lithium, lovastatin (case report), glucocorticoids (dose-related), mercaptopurine, sulfonamides, thiazide diuretics, and tolbutamide.

In addition, a number of medications have been noted to cause transient depression in TSH secretion, which may complicate interpretation of monitoring tests for levothyroxine, including corticosteroids, octreotide, and dopamine. Metoclopramide may increase TSH secretion

Anesthesia and Critical Care Concerns/Other Considerations

Equivalent dosing: Thyroid USP 60 mg ~ levothyroxine 0.05-0.06 mg ~ liothyronine 0.015-0.0375 mg

50-60 mg thyroid ~ 50-60 mcg levothyroxine and 12.5-15 mcg liothyronine Liotrix®

Note: Several medications have effects on thyroid production or conversion. The impact in thyroid replacement has not been specifically evaluated, but patient response should be monitored:

Methimazole: Decreases thyroid hormone secretion, while propylthiouracil decrease thyroid hormone secretion and decreases conversion of T4 to T3.

Beta-adrenergic antagonists: Decrease conversion of T4 to T3 (dose related, propranolol

160 mg/day); patients may be clinically euthyroid.

Iodide, iodine-containing radiographic contrast agents may decrease thyroid hormone secretion; may also increase thyroid hormone secretion, especially in patients with Graves' disease.

Other agents reported to impact on thyroid production/conversion include aminoglutethimide, amiodarone, chloral hydrate, diazepam, ethionamide, interferon-alpha, interleukin-2, lithium, lovastatin (case report), glucocorticoids (dose-related), mercaptopurine, sulfonamides, thiazide diuretics, and tolbutamide.

In addition, a number of medications have been noted to cause transient depression in TSH secretion, which may complicate interpretation of monitoring tests for levothyroxine, including corticosteroids, octreotide, and dopamine. Metoclopramide may increase TSH secretion

Soy protein may interfere with absorption of levothyroxine sodium. An enteral formula without soy protein should be selected and thyroid function monitored during tube feeding.

Cardiovascular Considerations

The treatment of patients with combined hypothyroidism and ischemic heart disease needs to be approached very carefully, preferably under the guidance of an endocrinologist and cardiologist. This is because administration of substantial doses of thyroid hormone may precipitate acute cardiac ischemia in patients who have been chronically hypothyroid. Therefore, recognizing that dosing regimens may vary, the general approach is to start at very low doses of thyroid supplementation with very gradual increases in dosage every 3-6 weeks. It is important that patients be monitored very carefully for development of cardiac ischemia during thyroid hormone supplementation. Similarly, patients with heart failure and hypothyroidism should be closely followed.

The possibility of underlying hypothyroidism (and also hyperthyroidism) should be considered in patients with atrial fibrillation. Correction of the underlying thyroid disorder may help in restoration of normal sinus rhythm. Hypothyroidism may also constitute an underlying etiology for obstructive sleep apnea.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported



Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No precautions with vasoconstrictor are necessary if patient is well controlled with levothyroxine



Mental Health: Effects on Mental Status

May rarely cause nervousness or insomnia



Mental Health: Effects on Psychiatric Treatment

Used to augment antidepressants; TCAs may increase toxic potential of both drugs



Dosage Forms

Injection, powder for reconstitution, as sodium: 0.2 mg, 0.5 mg

Synthroid® 0.2 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

References

Bauer LA, "Simulations of Levothyroxine Bioavailability Using a Single Dose Protocol,"Am J Therapeut, 1995, 2:414-6.

Berkner PD, Starkman H, and Person N, "Acute L-Thyroxine Overdose: Therapy With Sodium Ipodate: Evaluation of Clinical and Physiologic Parameters,"J Emerg Med, 1991, 9(3):129-31.

Binimelis J, Bassas L, Marruecos L, et al, "Massive Thyroxine Intoxication: Evaluation of Plasma Extraction,"Intens Care Med, 1987, 13(1):33-8.

Escalante DA, Arem N, and Arem R, "Assessment of Interchangeability of Two Brands of Levothyroxine Preparations With a Third-Generation TSH Assay,"Am J Med, 1995, 98(4):374-8.

Gorman RL, Chamberlain JM, Rose SR, et al, "Massive Levothyroxine Overdose: High Anxiety - Low Toxicity,"Pediatrics, 1988, 82(4):666-9.

Helfand M and Crapo LM, "Monitoring Therapy in Patients Taking Levothyroxine,"Ann Intern Med, 1990, 113(6):450-4.

Johnson DG and Campbell S, "Hormonal and Metabolic Agents,"Geriatric Pharmacology, Bressler R and Katz MD, eds, New York, NY: McGraw-Hill, 1993, 427-50.

Kulig K, Golightly LK, and Rumack BH, "Levothyroxine Overdose Associated With Seizures in a Young Child,"JAMA, 1985, 254(15):2109-10.

Mandel SH, Magnusson AR, Burton BT, et al, "Massive Levothyroxine Ingestion: Conservative Management,"Clin Pediatr (Phila), 1989, 28(8):374-6.

Mayor GH, Orlando T, and Kurtz N, "Limitations of Levothyroxine Bioequivalence Evaluation: Analysis of an Attempted Study,"Am J Therapeut, 1995, 2:417-32.

Sanders LR, "Pituitary, Thyroid, Adrenal and Parathyroid Diseases in the Elderly,"Geriatric Medicine, 1990, 475-87.

Sawin CT, Geller A, Hershman JM, et al, "The Aging Thyroid. The Use of Thyroid Hormone in Older Persons,"JAMA, 1989, 261(18):2653-5.

Singh N, Singh P, and Hershman J. "Effect of Calcium Carbonate on the Absorption of Levothyroxine,"JAMA, 2000, 283:2822-25.

Stockley IH, Drug Interactions, 5th ed, London, UK: Pharmaceutical Press, 1999.

Tunget CL, Clark RF, Turchen SG, et al, "Raising the Decontamination Level for Thyroid Hormone Ingestions,"Am J Emerg Med, 1995, 13(1):9-13.

Watts NB, "Use of a Sensitive Thyrotropin Assay for Monitoring Treatment With Levothyroxine,"Arch Intern Med, 1989, 149(2):309-12.

International Brand Names

Berlthyrox® (DE); Dexnon® (ES); Eferox® (DE, PL); Elthyrone® (BE, LU); Eltroxin® (CA, CH, CZ, DK, GB, HK, IE, IL, IN, KW, NL, NZ, PL, SG, SI, TH); Euthyrox® (AR, AT, BE, BR, CH, CO, CZ, DE, HR, HU, ID, LU, NL, PL, RO, RU, SE, SG, SI, TH); Eutirox® (CL, CR, EC, GT, HN, IT, MX, PA, SV); Letequatro® (PT); Letrox® (CY, CZ, EG, HU, JO, KW, LB, MA, MT, PL, SY, YU); Letter® (PT); Levaxin® (NO, SE); Levoroxin® (PL); Levothroid® (ES); Lévothyrox® (FR); Levothyroxine® (GB); Levotiron® (TR); Levotiroxina Fabra® (AR); Levotiroxina Sodica® (AR); Levotiroxina Sodica L.CH.® (CL); Lixin Henning® (DE); L-Thyrox® (DE); L-Thyroxin Berlin-Chemie® (RU); L-Thyroxin beta® (DE); L-Thyroxine® (BE); L-Thyroxine-Christiaens® (LU); L-Thyroxine Roche® (FR); L-Thyroxin Henning® (AT, DE, HU); L-Thyroxin® (RO); Oroxine® (AU, BD, SG); Pondtroxin® (TH); Puran T4® (BR); Synthroid® (BR, CA, CL); T4 Montpellier® (AR); Tefor® (TR); Tetroid® (BR); Thevier® (DE); Thyradin-S® (JP); Thyrax® (BE, ID, LU, NL, PL, RO); Thyrax Duotab® (PL); Thyrex® (AT); Thyro-4® (RO); Thyroid-S® (TH); Thyrosit® (TH); Thyroxine® (GB); Thyroxine-Lam Thong® (TH); Thyroxin® (FI); Thyroxin-Natrium® (NO); Tiracrin® (IT); Tiroidine® [tabs] (MX); Tirosint® (IT); Tiroxina Leo® (ES); Tiroxin® (CO); Tivoral® (YU); Vobenol® (SI)



Review Date: 1969-12-31 Reviewed By: Keywords: ,
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