levothyroxine (Synthroid, Levoxyl, Levothroid, Unithroid, Levolet, Novothyrox, Thyrotab)
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Introduction
Tradenames: Synthroid, Levoxyl, Levothroid, Unithroid, Levolet, Novothyrox, Thyrotab.[9]
* Generic equally effective as brand name[27]
Epidemiology
- <10% of new levothyroxine prescriptions are for overt hypothyroidism
Indications
- thyroid replacement (hypothyroidism)
- thyroid carcinoma
- goiter
- Hashimoto's thyroiditis[21]
Contraindications
Caution
- patients over 65
- patients with heart disease
- patients with borderline adrenal function (may precipitate adrenal insufficiency)
- subclinical hypothyroidism with serum TSH < 10 mIU/L[28]
Dosage
- hypothyroidism
- start: 50 ug PO QD; 25 ug QD cautious replacement
- 25 ug QD dose increases every 6 weeks
- max 300 ug/day
- administer on empty stomach, delay eating
- in morning on empty stomach at least 30-60 min before food[14][15]
- absorption is best when taken at least an hour before breakfast or coffee, after overnight fasting[5][16]
- absorption is best when taken before bedtime[18]
- delay iron supplement > 4 hours to minimize interaction resulting in diminished absorption[5]
- myxedema coma: load 400 ug IV, then 100-200 ug QD
- higher doses likely needed during pregnancy, on average 30-50%
- consider gastrointestinal disorder if levothyroxine doose requirement higher than expected
- celiac disease can inhibit levothyroxine absorption[3]
(replacement dose averages 1.7 ug/kg/day)
switching generics does not require dose adjustment[31]
Tabs: 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, 300 mg.
Powder for injection: 0.2 mg (10 mL), 0.5 mL (10 mL)
Pharmacokinetics
- oral absorption is variable
- FDA-approved brands equivalent[8]
- impaired gastric acid secretion diminishes absorption[12][13]
- highly protein bound, thyroid-binding globulin increases in parallel with estrogen (i.e. during pregnancy)
- slow onset of action
- prolonged duration of action
- peak effect occurs in 3-4 weeks
elimination via liver
Monitor
- serum TSH
- baseline then every 6-8 weeks until normal, then every 6-12 months[17]
- every 6 weeks to 3 months after change is dose or product
- change in patient health
- including positive pregnancy test[5]
- every 4-6 weeks patients > 50 years with cardiac disease
- every 2-4 weeks patients < 50 years with severe hypothyroidism
- free T4 if hypophysectomy &/or pituitary rediation therapy
Adverse effects
- most adverse reactions are dose-related & can be minimized by increasing the dose slowly
- uncommon (< 1%)
- nervousness, tremors, hand tremors, clumsiness, insomnia, headache
- palpitations, tachycardia, cardiac arrhythmias, chest pain, shortness of breath
- weight loss, increased appetite, diarrhea, constipation, abdominal cramps
- changes in menstrual cycle, muscle aches
- fever, sweating, hair loss
- signs of overdose
- headache
- palpitations
- chest pain (angina pectoris)
- sweating
- leg cramps
- heat intolerance
- weight loss
- diarrhea
- onset of signs & symptoms of toxicity may be delayed 3-10 days, due to delay of metabolism of T4 to the more active T3[30]
- TSH suppression may predispose patients to osteoporosis
- dose-related increased risk of fractures in the elderly[19]
Drug interactions
- inducers of cyt P450 increase catabolism of thyroxine thus increase thyroxine requirements
- phenytoin, carbamazepine, rifampin, phenobarbital
- sertraline allegedly increases catabolism of thyroxine[5], but it is an inhibitor rather than inducer of cyt P450s
- thyroxine may alter concentrations of warfarin, digoxin, insulin
- drugs that decrease absorption of thyroxine
- dietary fiber & bile acid sequestrants (psyllium, cholestyramine)
- ferrous sulfate (see dosage)
- sucralfate
- aluminum hydroxide
- calcium carbonate[26]
- proton pump inhibitors may inhibit absorption of levothyroxine in tablet form[23]
- switching to oral solution corrects impaired absorption
- soybean oil
- coffee (caffeinated or decaffeinated)
- increased thyroxine-binding globulin (TBG), thus diminishing free T4[7]
- decreased thyroxine-binding globulin (TBG), thus increasing free T4[7]
- propranolol & glucocorticoids may inhibit conversion of T3 to T4[10]
- statins in combination may diminish serum TSH (5 mIU/L in 3.7% of patients)[24]
- biotin* may cause in vitro interference with thyroid function testing
- separate levothyroxine dose from interfering medication by 4 hours[3]
* biotin is found in supplements for hair & nails[5]
- drug interaction(s) of levothyroxine with proton pump inhibitors
- drug interaction(s) of beta-adrenergic receptor antagonists with thyroid hormone
- drug interaction(s) of raloxifene with levothyroxine
Mechanism of action
- synthetic hormone identical to thyroxine (T4)
- thyroid hormones increase metabolic rate of tissues
- involved in regulation of growth & differentiation
More general terms
Additional terms
Component of
- levothyroxine/triiodothyronine
- desiccated thyroid (Armour, Niva, Apur, Renthyroid, Adthyza)
- thyroxine/triiodothyronine (Euthroid, Thyrolar)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998 Department of Veterans Affairs, VA National Formulary
- ↑ 3.0 3.1 3.2 Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 275
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Medical Knowledge Self Assessment Program (MKSAP) 11, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2015, 2018, 2023.
Medical Knowledge Self Assessment Program (MKSAP) 20 American College of Physicians, Philadelphia 2025 - ↑ Journal Watch 20(14): 114, 2000 Singh N et al Effect of calcium carbonate on the absorption of levothyroxine. JAMA 283:2822, 2000 PMID: https://pubmed.ncbi.nlm.nih.gov/10838651
- ↑ 7.0 7.1 7.2 Journal Watch 21(13):106, 2001 Arafah BM et al Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 344:1743, 2001 PMID: https://pubmed.ncbi.nlm.nih.gov/11396440
- ↑ 8.0 8.1 Prescriber's Letter 10(8):44 2003
- ↑ 9.0 9.1 Prescriber's Letter 11(10): 2004 Levothyroxine Sustitution Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=201013&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 Prescriber's Letter 12(5): 2005 Combination Liothyronine (T3) and Levothyroxine (T4) Supplementation for Hypothyroidism Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=210512&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Roos A, Linn-Rasker SP, van Domburg RT, Tijssen JP, Berghout A. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med. 2005 Aug 8-22;165(15):1714-20. PMID: https://pubmed.ncbi.nlm.nih.gov/16087818
- ↑ 12.0 12.1 Centanni M et al, Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N Engl J Med 2006; 354:1787 PMID: https://pubmed.ncbi.nlm.nih.gov/16641395
- ↑ 13.0 13.1 Prescriber's Letter 13(5): 2006 Levothyroxine Absorption in Patients with Reduced Gastric Acid Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220613&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 14.0 14.1 Lexi-Comp IncTHYROXINE
- ↑ 15.0 15.1 Prescriber's Letter 15(12): 2008 Drugs and Substances that Reduce Absorption of Levothyroxine Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=241209&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 16.0 16.1 Bach-Huynh T-G et al Timing of levothyroxine administration affects serum thyrotropin concentration. J Clin Endocrinol Metab 2009 Oct; 94:3905. PMID: https://pubmed.ncbi.nlm.nih.gov/19584184
- ↑ 17.0 17.1 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com18)
- ↑ 18.0 18.1 Bolk N et al Effects of Evening vs Morning Levothyroxine Intake A Randomized Double-blind Crossover Trial Arch Intern Med. 2010;170(22):1996-2003 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/21149757 <Internet> http://archinte.ama-assn.org/cgi/content/abstract/170/22/1996
- ↑ 19.0 19.1 Turner MR et al Levothyroxine dose and risk of fractures in older adults: nested case-control study BMJ 2011; 342:d2238 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/21527461 <Internet> http://www.bmj.com/content/342/bmj.d2238.full
Leese GP and Flynn RV Levothyroxine dose and fractures in older adults BMJ 2011; 342:d2250 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/21527462 <Internet> http://www.bmj.com/content/342/bmj.d2250 - ↑ Prescriber's Letter 19(11): 2012 Helping Patients Take Levothyroxine Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=281112&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 21.0 21.1 Deprecated Reference
- ↑ 22.0 22.1 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
- ↑ 23.0 23.1 Vita R et al. Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol Metab 2014 Dec; 99:4481 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/25259910 <Internet> http://press.endocrine.org/doi/abs/10.1210/jc.2014-2684
- ↑ 24.0 24.1 Irving SA et al Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). Clin Endocrinol. 2015;82(1):136-141. PMID: https://pubmed.ncbi.nlm.nih.gov/25040647
- ↑ Tahboub R, Arafah BM. Sex steroids and the thyroid. Best Pract Res Clin Endocrinol Metab. 2009 Dec;23(6):769-80. Review. PMID: https://pubmed.ncbi.nlm.nih.gov/19942152
- ↑ 26.0 26.1 Zamfirescu I, Carlson HE. Absorption of levothyroxine when coadministered with various calcium formulations. Thyroid. 2011 May;21(5):483-6. doi:http://dx.doi.org/ 10.1089/thy.2010.0296. PMID: https://pubmed.ncbi.nlm.nih.gov/21595516 Free PMC Article
- ↑ 27.0 27.1 Brito JP et al. Comparative effectiveness of generic vs brand-name levothyroxine in achieving normal thyrotropin levels. JAMA Netw Open 2020 Sep 30; 3:e2017645 PMID: https://pubmed.ncbi.nlm.nih.gov/32997127 PMCID: PMC7527873 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2771041
- ↑ 28.0 28.1 Brito JP, Ross JS, El Kawkgi OM et al Levothyroxine Use in the United States, 2008-2018. JAMA Intern Med. Published online June 21, 2021 PMID: https://pubmed.ncbi.nlm.nih.gov/34152370 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2781311
Silverstein WK, Grady D Overuse of Levothyroxine in Patients With Subclinical Hypothyroidism. Time to "Leve"-Out-Thyroxine. JAMA Intern Med. Published online June 21, 2021 PMID: https://pubmed.ncbi.nlm.nih.gov/34152358 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2781314 - ↑ 29.0 29.1 Brito JP et al. Levothyroxine use in the United States, 2008-2018. JAMA Intern Med 2021 Jun 21; PMID: https://pubmed.ncbi.nlm.nih.gov/34152370 PMCID: PMC8218227 (available on 2022-06-21) https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2781311
- ↑ 30.0 30.1 Windle ML Fast Five Quiz: Levothyroxine Medscape. October 7, 2021 https://reference.medscape.com/viewarticle/960226
- ↑ 31.0 31.1 Brito JP, Deng Y, Ross JS et al. Association between generic-to-generic levothyroxine switching and thyrotropin levels among US adults. JAMA Intern Med 2022 Feb 28; [e-pub]. PMID: https://pubmed.ncbi.nlm.nih.gov/35226058 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2789278
- ↑ Medscape: Levothyroxine https://reference.medscape.com/drug/synthroid-levoxyl-levothyroxine-342732