 | |
 | |
| Clinical data | |
|---|---|
| Trade names | Synthroid, Levoxyl, others |
| Other names | 3,5,3′,5′-Tetraiodo-L-thyronine |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682461 |
| License data | |
| Pregnancy category | |
| Routes of administration | By mouth,intravenous |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 40-80%[4] |
| Metabolism | Mainly in the liver, kidneys, brain, and muscles |
| Eliminationhalf-life | ca. 7 days (in hyperthyroidism 3–4 days, in hypothyroidism 9–10 days) |
| Excretion | Feces and urine |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.093 |
| Chemical and physical data | |
| Formula | C15H11I4NO4 |
| Molar mass | 776.874 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 231 to 233 °C (448 to 451 °F)[5] |
| Solubility in water | Slightly soluble (0.105 mg·mL−1 at 25 °C)[6] mg/mL (20 °C) |
| |
| |
Levothyroxine, also known asL-thyroxine, is a synthetic form of thethyroid hormone thyroxine (T4).[4][7] It is used to treatthyroid hormone deficiency (hypothyroidism), including a severe form known asmyxedema coma.[4] It may also be used to treat and prevent certain types ofthyroid tumors.[4] It is not indicated forweight loss.[4] Levothyroxine is takenorally (by mouth) or given byintravenous injection.[4] Levothyroxine has ahalf-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.[4]
Side effects from excessive doses include weight loss, trouble tolerating heat, sweating, anxiety, trouble sleeping,tremor, andfast heart rate.[4] Use is not recommended in people who have had a recentheart attack.[4] Use duringpregnancy has been found to be safe.[4] Dosing should be based on regular measurements ofthyroid-stimulating hormone (TSH) and T4 levels in the blood.[4] Much of the effect of levothyroxine is following its conversion totriiodothyronine (T3).[4]
Levothyroxine was first made in 1927.[7] It is on theWorld Health Organization's List of Essential Medicines.[8] Levothyroxine is available as ageneric medication.[4] In 2023, it was the third most commonly prescribed medication in the United States, with more than 80 million prescriptions.[9][10]
Levothyroxine is typically used to treathypothyroidism,[11] and is the treatment of choice for people with hypothyroidism[12] who often require lifelong thyroid hormone therapy.[13]
It may also be used to treatgoiter via its ability to lowerthyroid-stimulating hormone (TSH), which is considered goiter-inducing.[14][15] Levothyroxine is also used as interventional therapy in people withnodular thyroid disease orthyroid cancer to suppress TSH secretion.[16] A subset of people with hypothyroidism treated with an appropriate dose of levothyroxine will describe continuing symptoms despite TSH levels in the normal range.[13] In these people, further laboratory and clinical evaluation is warranted, as they may have another cause for their symptoms.[13] Furthermore, reviewing their medications and dietary supplements is important, as several medications can affect thyroid hormone levels.[13]
Levothyroxine is also used to treatsubclinical hypothyroidism, which is defined by an elevated TSH level and a normal-range free T4 level without symptoms.[13] Such people may be asymptomatic[13] and whether they should be treated is controversial.[12] One benefit of treating this population with levothyroxine therapy is preventing the development of hypothyroidism.[12] As such, treatment should be taken into account for patients with initial TSH levels above 10 mIU/L, people with elevatedthyroid peroxidase antibody titers, people with symptoms of hypothyroidism and TSH levels of 5–10 mIU/L, and women who are pregnant or want to become pregnant.[12] Oral dosing for patients with subclinical hypothyroidism is 1 μg/kg/day.[17]
It is also used to treatmyxedema coma, which is a severe form of hypothyroidism characterized by mental status changes and hypothermia.[13] As it is a medical emergency with a high mortality rate, it should be treated in the intensive-care unit[13] with thyroid hormone replacement and aggressive management of individual organ system complications.[12]
Dosages vary according to the age groups and the individual condition of the person, body weight, and compliance with the medication and diet. Other predictors of the required dosage aresex,body mass index,deiodinase activity (SPINA-GD), andetiology of hypothyroidism.[18] Annual or semiannual clinical evaluations and TSH monitoring are appropriate after dosing has been established.[19] Levothyroxine is taken on an empty stomach about half an hour to an hour before meals.[20] As such, thyroid replacement therapy is usually taken 30 minutes prior to eating in the morning.[13] For patients with trouble taking levothyroxine in the morning, bedtime dosing is effective, as well.[13] A study in 2015 showed greater efficacy of levothyroxine when taken at bedtime.[21] Doses of levothyroxine that normalize serum TSH may not normalize abnormal levels ofLDL cholesterol andtotal cholesterol.[22]
Poorcompliance in taking the medicine is the most common cause of elevated TSH levels in people receiving appropriate doses of levothyroxine.[13]
For older people (over 50 years old) and people with known or suspectedischemic heart disease, levothyroxine therapy should not be initiated at the full replacement dose.[23] Since thyroid hormone increases the heart's oxygen demand by increasing heart rate and contractility, starting at higher doses may cause anacute coronary syndrome or anabnormal heart rhythm.[13]
Hypothyroidism is common among pregnant women. A nationwide cohort study showed that 1.39% of all pregnant women in 2010 in Denmark received a prescription of levothyroxine during pregnancy.[24] According to the U.S.Food and Drug Administration pregnancy categories, levothyroxine has been assigned category A.[23] Given that no increased risk of congenital abnormalities has been demonstrated in pregnant women taking levothyroxine, therapy should be continued during pregnancy.[23] Furthermore, treatment should be immediately administered to women diagnosed with hypothyroidism during pregnancy, as hypothyroidism is associated with a higher rate of complications, such asspontaneous abortion,preeclampsia, andpremature birth.[23]
Thyroid hormone requirements increase during and last throughout pregnancy.[13] As such, pregnant women are recommended to increase to nine doses of levothyroxine each week, rather than the usual seven, as soon as their pregnancy is confirmed.[13] Repeat thyroid function tests should be done five weeks after the dosage is increased.[13]
While a minimal amount of thyroid hormones is found in breast milk, the amount does not influence infant plasma thyroid levels.[17] Furthermore, levothyroxine was not found to cause any adverse events to the infant or mother during breastfeeding.[17] Since adequate thyroid hormone concentrations are required to maintain normal lactation, appropriate levothyroxine doses should be administered during breastfeeding.[17]
Levothyroxine is safe and effective for children with hypothyroidism; the goal of treatment for children with hypothyroidism is to reach and preserve normal intellectual and physical development.[23]
Levothyroxine is contraindicated in people with hypersensitivity to levothyroxine sodium or any component of the formulation, people with acute myocardial infarction, and people withthyrotoxicosis of any etiology.[17] Levothyroxine is also contraindicated for people with uncorrectedadrenal insufficiency, as thyroid hormones may cause anacute adrenal crisis by increasing the metabolic clearance ofglucocorticoids.[23] For oral tablets, the inability to swallow capsules is an additional contraindication.[17]
Adverse events are generally caused by incorrect dosing. Long-term suppression of TSH values below normal values frequently causes cardiac side effects and contributes to decreases inbone mineral density (low TSH levels are also well known to contribute toosteoporosis).[25]
Too high a dose of levothyroxine causeshyperthyroidism.[20][26][27] Overdose can result in heartpalpitations, abdominal pain, nausea, anxiousness, confusion, agitation,insomnia, weight loss, and increased appetite.[28][26] Allergic reactions to the drug are characterized by symptoms such as difficulty breathing, shortness of breath, or swelling of the face and tongue. Acute overdose may causefever,hypoglycemia,heart failure,coma, and unrecognized adrenal insufficiency.[citation needed]
Acute massive overdose may be life-threatening; treatment should be symptomatic and supportive. Massive overdose can be associated with increasedsympathetic activity, thus may require treatment withbeta-blockers.[20]
The effects of overdosing appear 6 hours to 11 days after ingestion.[28]
Many foods and other substances can interfere with the absorption of thyroxine. Substances that reduce absorption arealuminium- andmagnesium-containingantacids,simethicone,sucralfate,cholestyramine,colestipol, andpolystyrene sulfonate.Sevelamer withcalcium carbonate may decrease the bioavailability of levothyroxine.[29]Grapefruit juice may delay the absorption of levothyroxine, but based on a study of 10 healthy people aged 20–30 (eight men, two women), it may not have a significant effect onbioavailability in young adults.[30][31] A study of eight women suggested that coffee may interfere with the intestinal absorption of levothyroxine, though at a level less than eating bran.[32] Certain other substances can cause adverse effects that may be severe. Combination of levothyroxine withketamine may causehypertension andtachycardia;[33] andtricyclic andtetracyclicantidepressants increase its toxicity.Soy,walnuts,fiber,calcium supplements, andiron supplements can also adversely affect absorption.[30] A study found thatcow's milk reduces levothyroxine absorption.[34]
To minimize interactions, a manufacturer of levothyroxine recommends after taking it, waiting 30 minutes to one hour before eating or drinking anything that is not water. They further recommend taking it in the morning on an empty stomach.[30]
Levothyroxine is a synthetic form of thyroxine (T4), which is secreted by thethyroid gland. Levothyroxine and thyroxine are chemically identical: natural thyroxine is also in the "levo" chiral form, the difference is only in terminological preference. T4 isbiosynthesized fromtyrosine. Approximately 5% of the US population suffers from over- or underproduction of T4 and T3. SeeThyroid hormones § Thyroid metabolism for more information on its biosynthesis.[citation needed]
Industrially, levothyroxine is made by chemical synthesis. Tyrosine is a common starting material.[35] The produced hormone is incorporated into drugs as its sodium salt, levothyroxine sodium. Solid drugs such as tablets contain the pentahydrate form of the salt.[36]
Dextrothyroxine is the mirror form of levothyroxine with the opposite, non-natural chirality.
T4 is aprohormone; T4 is a precursor to the hormone T3. T4 is a tetraiodide, T3 is a triiodide,triiodothyronine. The selenoenzymeiodothyronine deiodinase mediates the T4 → T3 conversion. T3-thyroxine is a unique example of an iodine compound essential for human health.[37][38] T3 binds tothyroid receptor proteins in thecell nucleus and causes metabolic effects through the control ofDNA transcription andprotein synthesis.[23]
Absorption of orally administered levothyroxine from the gastrointestinal tract ranges from 40 to 80%, with the majority of the drug absorbed from thejejunum and upperileum.[23] Levothyroxine absorption is increased by fasting and decreased in certain malabsorption syndromes, by certain foods, and with age. Dietary fiber decreases thebioavailability of the drug.[23]
Greater than 99% of circulating thyroid hormones are bound to plasma proteins includingthyroxine-binding globulin,transthyretin (previously called thyroxine-binding prealbumin), andalbumin.[17] Only free hormone is metabolically active.[17]
The primary pathway of thyroid hormone metabolism is through sequential deiodination.[23] The liver is the main site of T4 deiodination, and along with the kidneys, are responsible for about 80% of circulating T3.[39] In addition to deiodination, thyroid hormones are also excreted through the kidneys and metabolized through conjugation and glucuronidation and excreted directly into the bile and the gut, where they undergo enterohepatic recirculation.[17]
Half-life elimination is 6–7 days for people with normal lab results; 9–10 days for people with hypothyroidism; 3–4 days for people with hyperthyroidism.[17] Thyroid hormones are primarily eliminated by the kidneys (about 80%), with urinary excretion decreasing with age.[17] The remaining 20% of T4 is eliminated in the stool.[17]
Thyroxine was first isolated in pure form in 1914 at theMayo Clinic byEdward Calvin Kendall from extracts of hog thyroid glands.[40] The hormone wassynthesized in 1927 by British chemistsCharles Robert Harington andGeorge Barger.[41]
As of 2011[update], levothyroxine was the second-most commonly prescribed medication in the US,[42] with 23.8 million prescriptions filled each year.[43]
In 2023, it was the third most commonly prescribed medication in the United States, with more than 80 million prescriptions.[9][10]
Levothyroxine for systemic administration is available as an oral tablet, an intramuscular injection, and as a solution for intravenous infusion.[17] Furthermore, it is available as both brand-name and generic products.[13] While the FDA approved the use of generic levothyroxine for brand-name levothyroxine in 2004, the decision was met with disagreement by several medical associations.[13] TheAmerican Association of Clinical Endocrinologists (AACE), theEndocrine Society, and theAmerican Thyroid Association did not agree with the FDA that brand-name and generic formulations of levothyroxine werebioequivalent.[13] As such, people were recommended to be started and kept on either brand-name or generic levothyroxine formulations and not changed back and forth from one to the other.[13] For people who do switch products, their TSH and free T4 levels should be tested after six weeks to check that they are within the normal range.[13]
Brand names include Eltroxin, Euthyrox, Eutirox, Letrox, Levaxin, Lévothyrox, Levoxyl,L-thyroxine, Thyrax, and Thyrax Duotab in Europe; Thyrox and Thyronorm in South Asia; Euthyrox, Levoxyl, Synthroid, Tirosint, and Unithroid in North and South America; and Thyrin and Thyrolar in Bangladesh. Numerousgeneric versions also are available.[4]
A meta-analysis published in 2021 found that once weekly thyroxine is associated with less efficient control of hypothyroidism at six weeks.[44]
