Levothyroxine

{{Short description|Thyroid hormone medication}} {{About|levothyroxine as a medication|its role as a hormone|thyroxine|the family of thyroid hormones|thyroid hormones}} {{Use dmy dates|date=December 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | image = Levothyroxine 200.svg | image_class = skin-invert-image | width = | alt = | image2 = Levothyroxine-from-xtal-3D-bs-17.png | image_class2 = bg-transparent | width2 = | alt2 = | caption =  | pronounce = | tradename = Synthroid, Levoxyl, others | Drugs.com = {{Drugs.com|monograph|levothyroxine-sodium}} | MedlinePlus = a682461 | DailyMedID = Levothyroxine | pregnancy_AU = A | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Levothyroxine Use During Pregnancy | website=Drugs.com | date=31 July 2019 | url=https://www.drugs.com/pregnancy/levothyroxine.html | access-date=22 February 2020}}</ref> | pregnancy_category = | routes_of_administration = By mouth, intravenous | ATC_prefix = H03 | ATC_suffix = AA01 | ATC_supplemental = | legal_AU = S4 | legal_AU_comment = <ref>{{cite web|url=https://www.tga.gov.au/resources/prescription-medicines-registrations/thoxine-accord-healthcare-pty-ltd|title=THOXINE (Accord Healthcare Pty Ltd)|website=Therapeutic Goods Administration}}</ref> | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Regulatory Decision Summary - Tirosint | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00841 | access-date=7 June 2022}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx only | legal_US_comment = | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status =

| index2_label = as salt | CAS_number = 51-48-9 | CAS_supplemental = {{CAS|6106-07-6}} (levothyroxine sodium hydrate) | PubChem = 5819 | IUPHAR_ligand = | DrugBank = DB00451 | ChemSpiderID = 5614 | UNII = Q51BO43MG4 | KEGG = D08125 | KEGG2 = D01010 | ChEBI = 18332 | ChEMBL = 1624 | NIAID_ChemDB = | synonyms = 3,5,3′,5′-Tetraiodo-{{small|L}}-thyronine

| IUPAC_name = (''S'')-2-Amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid | C = 15 | H = 11 | I = 4 | N = 1 | O = 4 | SMILES = NC(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(O)=O | StdInChI = 1S/C15H11I4NO4/c16-8-4-7(5-9(17)13(8)21)24-14-10(18)1-6(2-11(14)19)3-12(20)15(22)23/h1-2,4-5,12,21H, 3,20H2, (H, 22,23)/t12-/m0/s1 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = XUIIKFGFIJCVMT-LBPRGKRZSA-N | density = | density_notes = | melting_point = 231 | melting_high = 233 | melting_notes = <ref>{{cite journal | vauthors = Harington CR | title = Chemistry of Thyroxine: Constitution and Synthesis of Desiodo-Thyroxine | journal = The Biochemical Journal | volume = 20 | issue = 2 | pages = 300–313 | year = 1926 | pmid = 16743659 | pmc = 1251714 | doi = 10.1042/bj0200300 }}</ref> | boiling_point = | boiling_notes = | solubility = Slightly soluble (0.105 mg·mL−1 at 25 °C)<ref name="DrugBank">{{DrugBank|DB00451}}</ref> | specific_rotation = }}

'''Levothyroxine''', also known as '''{{small|L}}-thyroxine''', is a synthetic form of the thyroid hormone thyroxine (T4).<ref name=AHFS2016/><ref name=King2010/> It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma.<ref name=AHFS2016/> It may also be used to treat and prevent certain types of thyroid tumors.<ref name=AHFS2016/> It is not indicated for weight loss.<ref name=AHFS2016/> Levothyroxine is taken orally (by mouth) or given by intravenous injection.<ref name=AHFS2016/> Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.<ref name=AHFS2016/>

Side effects from excessive doses include weight loss, trouble tolerating heat, sweating, anxiety, trouble sleeping, tremor, and fast heart rate.<ref name=AHFS2016/> Use is not recommended in people who have had a recent heart attack.<ref name=AHFS2016/> Use during pregnancy has been found to be safe.<ref name=AHFS2016/> Dosing should be based on regular measurements of thyroid-stimulating hormone (TSH) and T4 levels in the blood.<ref name=AHFS2016/> Much of the effect of levothyroxine is following its conversion to triiodothyronine (T3).<ref name=AHFS2016>{{cite web|title=Levothyroxine Sodium|url=https://www.drugs.com/monograph/levothyroxine-sodium.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221013136/https://www.drugs.com/monograph/levothyroxine-sodium.html|archive-date=21 December 2016}}</ref>

Levothyroxine was first made in 1927.<ref name=King2010>{{cite book| vauthors = King TL, Brucker MC |title=Pharmacology for Women's Health|date=2010|publisher=Jones & Bartlett Publishers|isbn=978-1-4496-5800-7|page=544|url=https://books.google.com/books?id=E9qVyrNPsBkC&pg=PA544|url-status=live|archive-url=https://web.archive.org/web/20170910234123/https://books.google.com/books?id=E9qVyrNPsBkC&pg=PA544|archive-date=10 September 2017}}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> Levothyroxine is available as a generic medication.<ref name=AHFS2016/> In 2023, it was the third most commonly prescribed medication in the United States, with more than 80{{nbsp}}million prescriptions.<ref name="Top 300 of 2023">{{cite web | title=The Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref name="Levothyroxine - Drug Usage Statistics">{{cite web | title = Levothyroxine Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Levothyroxine | access-date = 17 August 2025 }}</ref>

== Medical uses == Levothyroxine is typically used to treat hypothyroidism,<ref name="pmid18662921">{{cite journal | vauthors = Vaidya B, Pearce SH | title = Management of hypothyroidism in adults | journal = BMJ | volume = 337 | pages = a801 | date = July 2008 | pmid = 18662921 | doi = 10.1136/bmj.a801 | s2cid = 33308816 }}</ref> and is the treatment of choice for people with hypothyroidism<ref name=Roberts>{{cite journal | vauthors = Roberts CG, Ladenson PW | title = Hypothyroidism | journal = Lancet | volume = 363 | issue = 9411 | pages = 793–803 | date = March 2004 | pmid = 15016491 | doi = 10.1016/S0140-6736(04)15696-1 | s2cid = 208792613 }}</ref> who often require lifelong thyroid hormone therapy.<ref name=Gaitonde>{{cite journal | vauthors = Gaitonde DY, Rowley KD, Sweeney LB | title = Hypothyroidism: an update | journal = American Family Physician | volume = 86 | issue = 3 | pages = 244–251 | date = August 2012 | pmid = 22962987 | url = https://www.aafp.org/afp/2012/0801/p244.html }}</ref>

It may also be used to treat goiter via its ability to lower thyroid-stimulating hormone (TSH), which is considered goiter-inducing.<ref name="pmid16507633">{{cite journal | vauthors = Svensson J, Ericsson UB, Nilsson P, Olsson C, Jonsson B, Lindberg B, Ivarsson SA | title = Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 5 | pages = 1729–1734 | date = May 2006 | pmid = 16507633 | doi = 10.1210/jc.2005-2400 | doi-access = free }}</ref><ref name=Dietlein_2007>{{cite journal | vauthors = Dietlein M, Wegscheider K, Vaupel R, Schmidt M, Schicha H | title = Management of multinodular goiter in Germany (Papillon 2005): do the approaches of thyroid specialists and primary care practitioners differ? | journal = Nuklearmedizin | volume = 46 | issue = 3 | pages = 65–75 | year = 2007 | pmid = 17549317 | doi = 10.1160/nukmed-0068 | s2cid = 23972101 }}</ref> Levothyroxine is also used as interventional therapy in people with nodular thyroid disease or thyroid cancer to suppress TSH secretion.<ref name=Mandel>{{cite journal | vauthors = Mandel SJ, Brent GA, Larsen PR | title = Levothyroxine therapy in patients with thyroid disease | journal = Annals of Internal Medicine | volume = 119 | issue = 6 | pages = 492–502 | date = September 1993 | pmid = 8357116 | doi = 10.7326/0003-4819-119-6-199309150-00009 | s2cid = 2889757 }}</ref> A subset of people with hypothyroidism treated with an appropriate dose of levothyroxine will describe continuing symptoms despite TSH levels in the normal range.<ref name="Gaitonde" /> In these people, further laboratory and clinical evaluation is warranted, as they may have another cause for their symptoms.<ref name="Gaitonde" /> Furthermore, reviewing their medications and dietary supplements is important, as several medications can affect thyroid hormone levels.<ref name="Gaitonde" />

Levothyroxine is also used to treat subclinical hypothyroidism, which is defined by an elevated TSH level and a normal-range free T4 level without symptoms.<ref name="Gaitonde" /> Such people may be asymptomatic<ref name="Gaitonde" /> and whether they should be treated is controversial.<ref name="Roberts" /> One benefit of treating this population with levothyroxine therapy is preventing the development of hypothyroidism.<ref name="Roberts" /> As such, treatment should be taken into account for patients with initial TSH levels above 10 mIU/L, people with elevated thyroid 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.<ref name="Roberts" /> Oral dosing for patients with subclinical hypothyroidism is 1 μg/kg/day.<ref name="LexiComp" />

It is also used to treat myxedema coma, which is a severe form of hypothyroidism characterized by mental status changes and hypothermia.<ref name="Gaitonde" /> As it is a medical emergency with a high mortality rate, it should be treated in the intensive-care unit<ref name="Gaitonde" /> with thyroid hormone replacement and aggressive management of individual organ system complications.<ref name="Roberts" /> thumb|Generic levothyroxine, 25-μg oral tablet

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 are sex, body mass index, deiodinase activity (SPINA-GD), and etiology of hypothyroidism.<ref name=pmid26335522>{{cite journal | vauthors = Midgley JE, Larisch R, Dietrich JW, Hoermann R | title = Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency | journal = Endocrine Connections | volume = 4 | issue = 4 | pages = 196–205 | date = December 2015 | pmid = 26335522 | pmc = 4557078 | doi = 10.1530/EC-15-0056 }}</ref> Annual or semiannual clinical evaluations and TSH monitoring are appropriate after dosing has been established.<ref>{{EMedicine|article|122393|Hypothyroidism|treatment}}</ref> Levothyroxine is taken on an empty stomach about half an hour to an hour before meals.<ref name="RxList" /> As such, thyroid replacement therapy is usually taken 30 minutes prior to eating in the morning.<ref name="Gaitonde" /> For patients with trouble taking levothyroxine in the morning, bedtime dosing is effective, as well.<ref name="Gaitonde" /> A study in 2015 showed greater efficacy of levothyroxine when taken at bedtime.<ref>{{Cite news | title = Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial | url = http://archinte.jamanetwork.com/article.aspx?articleid=776486 | url-status = live | archive-url = https://web.archive.org/web/20150906163348/http://archinte.jamanetwork.com/article.aspx?articleid=776486 | archive-date = 6 September 2015 }}</ref> Doses of levothyroxine that normalize serum TSH may not normalize abnormal levels of LDL cholesterol and total cholesterol.<ref>{{cite journal | vauthors = McAninch EA, Rajan KB, Miller CH, Bianco AC | title = Systemic Thyroid Hormone Status During Levothyroxine Therapy In Hypothyroidism: A Systematic Review and Meta-Analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 12 | pages = 4533–4542 | date = August 2018 | pmid = 30124904 | pmc = 6226605 | doi = 10.1210/jc.2018-01361 }}</ref>

Poor compliance in taking the medicine is the most common cause of elevated TSH levels in people receiving appropriate doses of levothyroxine.<ref name="Gaitonde" />

=== 50 and older === For older people (over 50 years old) and people with known or suspected ischemic heart disease, levothyroxine therapy should not be initiated at the full replacement dose.<ref name=Novothyrox>{{Cite web | title = Novothyrox (levothyroxine sodium tablets, USP) | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021292s002lbl.pdf | access-date = 20 April 2014 | url-status = dead | archive-url = https://web.archive.org/web/20130307010006/http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021292s002lbl.pdf | archive-date = 7 March 2013 }}</ref> Since thyroid hormone increases the heart's oxygen demand by increasing heart rate and contractility, starting at higher doses may cause an acute coronary syndrome or an abnormal heart rhythm.<ref name="Gaitonde" />

=== Pregnancy and breastfeeding === 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.<ref>{{cite journal | vauthors = Gidén K, Andersen JT, Torp-Pedersen AL, Enghusen Poulsen H, Torp-Pedersen C, Jimenez-Solem E | title = Use of thyroid hormones in relation to pregnancy: a Danish nationwide cohort study | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 94 | issue = 6 | pages = 591–597 | date = June 2015 | pmid = 25732102 | doi = 10.1111/aogs.12621 | s2cid = 5525921 | doi-access = free }}</ref> According to the U.S. Food and Drug Administration pregnancy categories, levothyroxine has been assigned category A.<ref name="Novothyrox" /> Given that no increased risk of congenital abnormalities has been demonstrated in pregnant women taking levothyroxine, therapy should be continued during pregnancy.<ref name="Novothyrox" /> Furthermore, treatment should be immediately administered to women diagnosed with hypothyroidism during pregnancy, as hypothyroidism is associated with a higher rate of complications, such as spontaneous abortion, preeclampsia, and premature birth.<ref name="Novothyrox" />

Thyroid hormone requirements increase during and last throughout pregnancy.<ref name="Gaitonde" /> 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.<ref name="Gaitonde" /> Repeat thyroid function tests should be done five weeks after the dosage is increased.<ref name="Gaitonde" />

While a minimal amount of thyroid hormones is found in breast milk, the amount does not influence infant plasma thyroid levels.<ref name="LexiComp" /> Furthermore, levothyroxine was not found to cause any adverse events to the infant or mother during breastfeeding.<ref name="LexiComp" /> Since adequate thyroid hormone concentrations are required to maintain normal lactation, appropriate levothyroxine doses should be administered during breastfeeding.<ref name="LexiComp" />

=== Children === 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.<ref name="Novothyrox" />

== Contraindications == Levothyroxine is contraindicated in people with hypersensitivity to levothyroxine sodium or any component of the formulation, people with acute myocardial infarction, and people with thyrotoxicosis of any etiology.<ref name="LexiComp" /> Levothyroxine is also contraindicated for people with uncorrected adrenal insufficiency, as thyroid hormones may cause an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids.<ref name="Novothyrox" /> For oral tablets, the inability to swallow capsules is an additional contraindication.<ref name="LexiComp" />

==Side effects== 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 in bone mineral density (low TSH levels are also well known to contribute to osteoporosis).<ref name=Frilling_2004>{{cite journal | vauthors = Frilling A, Liu C, Weber F | title = Benign multinodular goiter | journal = Scandinavian Journal of Surgery | volume = 93 | issue = 4 | pages = 278–281 | year = 2004 | pmid = 15658668 | doi = 10.1177/145749690409300405 | s2cid = 38834260 }}</ref>

Too high a dose of levothyroxine causes hyperthyroidism.<ref name="RxList">{{Cite web | title = Synthroid (Levothyroxine Sodium) Drug Information: Uses, Side Effects, Drug Interactions and Warnings | publisher = RxList | url = http://www.rxlist.com/synthroid-drug.htm | access-date = 18 July 2010 | url-status = live | archive-url = https://web.archive.org/web/20100511145303/http://www.rxlist.com/synthroid-drug.htm | archive-date = 11 May 2010 }}</ref><ref name="Levoxyl label">{{cite web | title=Levoxyl- levothyroxine sodium tablet | website=DailyMed | date=31 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=758588c3-c63e-491b-0aa2-4f50d80cb174 | access-date=21 February 2020}}</ref><ref name="Synthroid label">{{cite web | title=Synthroid- levothyroxine sodium tablet | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e11ad30-1041-4520-10b0-8f9d30d30fcc | access-date=21 February 2020}}</ref> Overdose can result in heart palpitations, abdominal pain, nausea, anxiousness, confusion, agitation, insomnia, weight loss, and increased appetite.<ref name=Toxicity /><ref name="Levoxyl label" /> 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 cause fever, hypoglycemia, heart failure, coma, and unrecognized adrenal insufficiency.{{cn|date=July 2024}}

Acute massive overdose may be life-threatening; treatment should be symptomatic and supportive. Massive overdose can be associated with increased sympathetic activity, thus may require treatment with beta-blockers.<ref name="RxList" />

The effects of overdosing appear 6 hours to 11 days after ingestion.<ref name=Toxicity>{{Cite web | title = Toxicity, Thyroid Hormone | vauthors = Irizarry L | publisher = WebMd | url = http://www.emedicine.com/emerg/TOPIC800.HTM | date = 23 April 2010 | access-date = 31 October 2010 | url-status = live | archive-url = https://web.archive.org/web/20081014025341/http://www.emedicine.com/emerg/TOPIC800.HTM | archive-date = 14 October 2008 }}</ref>

== Interactions ==

Many foods and other substances can interfere with the absorption of thyroxine. Substances that reduce absorption are aluminium- and magnesium-containing antacids, simethicone, sucralfate, cholestyramine, colestipol, and polystyrene sulfonate. Sevelamer with calcium carbonate may decrease the bioavailability of levothyroxine.<ref>{{cite journal | vauthors = Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB | title = Effect of phosphate binders upon TSH and L-thyroxine dose in patients on thyroid replacement | journal = International Urology and Nephrology | volume = 39 | issue = 2 | pages = 599–602 | date = 2007 | pmid = 17216296 | doi = 10.1007/s11255-006-9166-6 | s2cid = 3092250 }}</ref> 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 on bioavailability in young adults.<ref name="Taking synthroid the right way" /><ref name="pmid16120075">{{cite journal | vauthors = Lilja JJ, Laitinen K, Neuvonen PJ | title = Effects of grapefruit juice on the absorption of levothyroxine | journal = British Journal of Clinical Pharmacology | volume = 60 | issue = 3 | pages = 337–341 | date = September 2005 | pmid = 16120075 | pmc = 1884777 | doi = 10.1111/j.1365-2125.2005.02433.x }}</ref> A study of eight women suggested that coffee may interfere with the intestinal absorption of levothyroxine, though at a level less than eating bran.<ref name="Benvenga">{{cite journal | vauthors = Benvenga S, Bartolone L, Pappalardo MA, Russo A, Lapa D, Giorgianni G, Saraceno G, Trimarchi F | title = Altered intestinal absorption of L-thyroxine caused by coffee | journal = Thyroid | volume = 18 | issue = 3 | pages = 293–301 | date = March 2008 | pmid = 18341376 | doi = 10.1089/thy.2007.0222 | publisher = Mary Ann Liebert }}</ref> Certain other substances can cause adverse effects that may be severe. Combination of levothyroxine with ketamine may cause hypertension and tachycardia;<ref name="Austria-Codex">{{Cite book | title = Austria-Codex | edition = 62nd | veditors = Jasek W | year = 2007 | language = de | publisher = Österreichischer Apothekerverlag | location = Vienna | pages = 8133–4 | isbn = 978-3-85200-181-4}}</ref> and tricyclic and tetracyclic antidepressants increase its toxicity. Soy,  walnuts, fiber, calcium supplements, and iron supplements can also adversely affect absorption.<ref name="Taking synthroid the right way" /> A study found that cow's milk reduces levothyroxine absorption.<ref name="Milk">{{cite web | vauthors = Biscaldi L |title=Oral Levothyroxine Absorption Reduced By Cow's Milk Consumption |url=https://www.endocrinologyadvisor.com/home/conference-highlights/endo-2017/oral-levothyroxine-absorption-reduced-by-cows-milk-consumption/ |website=endocrinologyadvisor |date=2 April 2017 |access-date=18 February 2020}}</ref>

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.<ref name="Taking synthroid the right way">{{cite web |title=Taking synthroid the right way |url=https://www.synthroid.com/starting/taking-synthroid-the-right-way |website=Synthroid |access-date=18 February 2020}}</ref>

== Chemistry == Levothyroxine is a synthetic form of thyroxine (T4), which is secreted by the thyroid gland. Levothyroxine and thyroxine are chemically identical:<ref>{{cite web |title=Levothyroxine |url=https://go.drugbank.com/drugs/DB00451 |website=DrugBank |access-date=5 December 2025}}</ref> natural thyroxine is also in the "levo" chiral form, the difference is only in terminological preference. T4 is biosynthesized from tyrosine. Approximately 5% of the US population suffers from over- or underproduction of T{{sub|4}} and T{{sub|3}}.{{cn|date=July 2024}} See {{section link|Thyroid hormones|Thyroid metabolism}} for more information on its biosynthesis.

Industrially, levothyroxine is made by chemical synthesis. Tyrosine is a common starting material.<ref>{{cite journal | doi=10.7598/cst2016.1288 | title=Synthesis and Characterization of Potential Impurities in Levothyroxine | journal=Chemical Science Transactions | date=2016 }}</ref> 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.<ref>{{cite journal | vauthors = Barreira A, Santos AF, Dionísio M, Jesus AR, Duarte AR, Petrovski Ž, Paninho AB, Ventura MG, Branco LC | title = Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies | journal = International Journal of Molecular Sciences | volume = 24 | issue = 10 | page = 8822 | date = May 2023 | pmid = 37240166 | pmc = 10218257 | doi = 10.3390/ijms24108822 | doi-access = free }}</ref>

Dextrothyroxine is the mirror form of levothyroxine with the opposite, non-natural chirality.

==Mechanism of action== T{{sub|4}} is a {{nowrap|prohormone{{px2}}{{mdash}}{{px2}}}}‌a precursor to the hormone T{{sub|3}}. While T{{sub|4}} is a tetraiodide, T{{sub|3}} is a triiodide known as triiodothyronine. The selenoenzyme iodothyronine deiodinase mediates the T{{sub|4}}{{px2}}→{{px2}}T{{sub|3}} conversion. T{{sub|3}}-thyroxine is a unique example of an iodine compound essential for human health.<ref>{{cite journal | vauthors = Carvalho DP, Dupuy C | title = Thyroid hormone biosynthesis and release | journal = Molecular and Cellular Endocrinology | volume = 458 | pages = 6–15 | date = December 2017 | pmid = 28153798 | doi = 10.1016/j.mce.2017.01.038 | s2cid = 31150531 }}</ref><ref>{{cite journal | vauthors = Mondal S, Raja K, Schweizer U, Mugesh G | title = Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones | journal = Angewandte Chemie | volume = 55 | issue = 27 | pages = 7606–7630 | date = June 2016 | pmid = 27226395 | doi = 10.1002/anie.201601116 | bibcode = 2016ACIE...55.7606M }}</ref> T{{sub|3}} binds to thyroid receptor proteins in the cell nucleus and causes metabolic effects through the control of DNA transcription and protein synthesis.<ref name="Novothyrox" />

== Pharmacokinetics == Absorption of orally administered levothyroxine from the gastrointestinal tract ranges from 40 to 80%, with the majority of the drug absorbed from the jejunum and upper ileum.<ref name="Novothyrox" /> Levothyroxine absorption is increased by fasting and decreased in certain malabsorption syndromes, by certain foods, and with age. Dietary fiber decreases the bioavailability of the drug.<ref name="Novothyrox" />

Greater than 99% of circulating thyroid hormones are bound to plasma proteins including thyroxine-binding globulin, transthyretin (previously called thyroxine-binding prealbumin), and albumin.<ref name="LexiComp" /> Only free hormone is metabolically active.<ref name="LexiComp" />

The primary pathway of thyroid hormone metabolism is through sequential deiodination.<ref name="Novothyrox" /> The liver is the main site of T4 deiodination, and along with the kidneys, are responsible for about 80% of circulating T3.<ref name=Sherwood7thEd>{{Cite book | chapter = 19 The Peripheral Endocrine Glands | vauthors = Sherwood L | title = Human Physiology | year = 2010 | publisher = Brooks/Cole | page = 694 | isbn = 978-0-495-39184-5}}</ref> 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.<ref name="LexiComp" />

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.<ref name="LexiComp" /> Thyroid hormones are primarily eliminated by the kidneys (about 80%), with urinary excretion decreasing with age.<ref name="LexiComp" /> The remaining 20% of T4 is eliminated in the stool.<ref name="LexiComp" />

==History== Thyroxine was first isolated in pure form in 1914 at the Mayo Clinic by Edward Calvin Kendall from extracts of hog thyroid glands.<ref>{{Cite journal | title = The isolation in crystalline form of the compound containing iodin, which occurs in the thyroid: Its chemical nature and physiologic activity | vauthors = Kendall EC | journal = Journal of the American Medical Association | year = 1915 | volume = 64 | issue = 25 | pages = 2042–2043 | doi = 10.1001/jama.1915.02570510018005| url = https://zenodo.org/record/1423411 }}</ref> The hormone was synthesized in 1927 by British chemists Charles Robert Harington and George Barger.<ref>{{cite journal | vauthors = Slater S | title = The discovery of thyroid replacement therapy. Part 3: A complete transformation | journal = Journal of the Royal Society of Medicine | volume = 104 | issue = 3 | pages = 100–106 | date = March 2011 | pmid = 21357978 | pmc = 3046199 | doi = 10.1258/jrsm.2010.10k052 }}</ref>

==Society and culture==

===Economics=== [[File:Generic Euthyrox.jpg|thumb|right|A 30 tablet blister pack package of generic Euthyrox (levothyroxine) manufactured by Merck KGaA and marketed by Provell Pharmaceuticals in the US]] {{As of|2011}}, levothyroxine was the second-most commonly prescribed medication in the US,<ref name=Kleinrock>{{Cite web | title = The Use of Medicines in the United States: Review of 2011 | vauthors = Kleinrock M | publisher = IMS Institute for Healthcare Informatics | url = http://www.environmentalhealthnews.org/ehs/news/2013/pdf-links/IHII_Medicines_in_U.S_Report_2011-1.pdf | access-date = 20 April 2014 | url-status = dead | archive-url = https://web.archive.org/web/20131126174323/http://www.environmentalhealthnews.org/ehs/news/2013/pdf-links/IHII_Medicines_in_U.S_Report_2011-1.pdf | archive-date = 26 November 2013 }}</ref> with 23.8 million prescriptions filled each year.<ref name=Moore>{{Cite web | title = Monitoring FDA MedWatch Reports: Signals for Dabigatran and Metoclopramide | vauthors = Moore T | work = QuarterWatch | publisher = Institute for Safe Medication Practices | url = http://www.ismp.org/quarterwatch/pdfs/2011Q1.pdf | access-date = 20 April 2014 | url-status = live | archive-url = https://web.archive.org/web/20130925064909/http://ismp.org/quarterwatch/pdfs/2011Q1.pdf | archive-date = 25 September 2013 }}</ref>

In 2023, it was the third most commonly prescribed medication in the United States, with more than 80{{nbsp}}million prescriptions.<ref name="Top 300 of 2023" /><ref name="Levothyroxine - Drug Usage Statistics" />

===Available forms=== Levothyroxine for systemic administration is available as an oral tablet, an intramuscular injection, and as a solution for intravenous infusion.<ref name=LexiComp>{{Cite web | title = Levothyroxine (Lexi-Drugs) | work = LexiComp | url = http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7172 | access-date = 20 April 2014 | url-status = live | archive-url = https://web.archive.org/web/20140929172946/http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7172 | archive-date = 29 September 2014 }}</ref> Furthermore, it is available as both brand-name and generic products.<ref name="Gaitonde" /> 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.<ref name="Gaitonde" /> The American Association of Clinical Endocrinologists (AACE), the Endocrine Society, and the American Thyroid Association did not agree with the FDA that brand-name and generic formulations of levothyroxine were bioequivalent.<ref name="Gaitonde" /> 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.<ref name="Gaitonde" /> 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.<ref name="Gaitonde" />

Brand names include Eltroxin, Euthyrox, Eutirox, Letrox, Levaxin, Lévothyrox, Levoxyl, {{small|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. Numerous generic versions also are available.<ref name=AHFS2016/>

== Research == A meta-analysis published in 2021 found that once weekly thyroxine is associated with less efficient control of hypothyroidism at six weeks.<ref>{{cite journal | vauthors = Dutta D, Jindal R, Kumar M, Mehta D, Dhall A, Sharma M | title = Efficacy and Safety of Once Weekly Thyroxine as Compared to Daily Thyroxine in Managing Primary Hypothyroidism: A Systematic Review and Meta-Analysis | journal = Indian Journal of Endocrinology and Metabolism | volume = 25 | issue = 2 | pages = 76–85 | date = 2021 | pmid = 34660234 | pmc = 8477739 | doi = 10.4103/ijem.IJEM_789_20 | doi-access = free | title-link = doi }}</ref>

== References == {{Reflist}}

== External links == * {{cite web | title=Real-world Evidence from a Narrow Therapeutic Index Product (Levothyroxine) Reflects the Therapeutic Equivalence of Generic Drug Products | website=U.S. Food and Drug Administration (FDA) | date=19 November 2020 | url=https://www.fda.gov/drugs/news-events-human-drugs/real-world-evidence-narrow-therapeutic-index-product-levothyroxine-reflects-therapeutic-equivalence | archive-url=https://web.archive.org/web/20201002210651/https://www.fda.gov/drugs/news-events-human-drugs/real-world-evidence-narrow-therapeutic-index-product-levothyroxine-reflects-therapeutic-equivalence | url-status=dead | archive-date=2 October 2020 }} * [https://medspeakpro.org/terms/levothyroxine/ Levothyroxine pronunciation guide – audio, phonetic spelling, and syllable breakdown]

{{Thyroid therapy}} {{Hormones}} {{Thyroid hormone receptor modulators}} {{Xenobiotic-sensing receptor modulators}} {{Merck Serono|state=autocollapse}} {{Portal bar | Medicine}} {{Authority control}}

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