Letrozole Explained

Watchedfields:changed
Verifiedrevid:460779010
Width:225
Width2:225
Tradename:Femara, others
Dailymedid:Letrozole
Routes Of Administration:By mouth
Class:Aromatase inhibitor
Antiestrogen
Atc Prefix:L02
Atc Suffix:BG04
Legal Ca:Schedule VII
Legal Uk:POM
Legal Us:Rx-only
Legal Us Comment:[1]
Legal Eu:Rx-only
Legal Eu Comment:[2]
Bioavailability:99.9%
Protein Bound:60%, mainly to albumin
Metabolism:pharmacologically-inactive metabolites Bis(4-cyanophenyl)methanol and 4,4'-dicyanobenzophenone.[3]
Elimination Half-Life:2 days
Excretion:Kidney
Cas Number:112809-51-5
Pubchem:3902
Iuphar Ligand:5209
Drugbank:DB01006
Chemspiderid:3765
Unii:7LKK855W8I
Kegg:D00964
Chebi:6413
Chembl:1444
Iupac Name:4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile
C:17
H:11
N:5
Smiles:N#Cc1ccc(cc1)C(c2ccc(C#N)cc2)n3ncnc3
Stdinchi:1S/C17H11N5/c18-9-13-1-5-15(6-2-13)17(22-12-20-11-21-22)16-7-3-14(10-19)4-8-16/h1-8,11-12,17H
Stdinchikey:HPJKCIUCZWXJDR-UHFFFAOYSA-N

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer.

It was patented in 1986 and approved for medical use in 1996.[4] In 2021, it was the 222nd most commonly prescribed medication in the United States, with more than 1million prescriptions.[5] [6] It is on the World Health Organization's List of Essential Medicines.[7]

Medical uses

Breast cancer

Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women.[8]

Comparison with tamoxifen

Tamoxifen is also used to treat hormonally-responsive breast cancer, but it does so by interfering with the estrogen receptor. However, letrozole is effective only in post-menopausal women, in whom estrogen is produced predominantly in peripheral tissues (i.e. in adipose tissue, like that of the breast) and a number of sites in the brain.[9] In pre-menopausal women, the main source of estrogen is from the ovaries not the peripheral tissues, and letrozole is ineffective.

In the BIG 1–98 Study, of post-menopausal women with hormonally-responsive breast cancer, letrozole reduced the recurrence of cancer, but did not change survival rate, compared to tamoxifen.[10] [11]

Ovulation induction

Letrozole has been used for ovulation induction by fertility doctors since 2001, because it has fewer side-effects than clomiphene (Clomid) and less chance of multiple gestation. A study of 150 babies following treatment with either letrozole alone or letrozole and gonadotropins presented at the American Society of Reproductive Medicine 2005 Conference found no difference in overall abnormalities but did find a significantly higher rate of locomotor and cardiac abnormalities among the group having taken letrozole compared to natural conception.[12] A larger, follow-up study with 911 babies compared those born following treatment with letrozole to those born following treatment with clomiphene.[13] That study also found no significant difference in the rate of overall abnormalities, but found that congenital cardiac anomalies was significantly higher in the clomiphene group compared to the letrozole group. Despite this, India banned the usage of letrozole in 2011, citing potential risks to infants.[14] In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozole's makers to approve the drug for infertility in India and also stated that letrozole's use for infertility was illegal worldwide;[15] however, such off-label uses are legal in many countries such as the US and UK.[16] [17]

Medical Abortion

Tests have shown that the efficacy of first-trimester medical abortions (using misoprostol) can be improved by including letrozole in the drug regimen.[18] [19] [20]

Contraindications

Letrozole is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation.[21]

Side effects

The most common side effects are sweating, hot flushes, arthralgia (joint pain), and fatigue.

Generally, side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, which is why in certain patient populations such as post-menopausal women or osteoporotics, bisphosphonates may also be prescribed.

Interactions

Letrozole inhibits the liver enzyme CYP2A6, and to a lesser extent CYP2C19, in vitro, but no relevant interactions with drugs like cimetidine and warfarin have been observed.

Pharmacology

Pharmacodynamics

Letrozole is an orally active, nonsteroidal, selective aromatase inhibitor and hence an antiestrogen. It prevents aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of corticosteroids.

Research

The antiestrogen action of letrozole has been shown to be useful in pretreatment for termination of pregnancy, in combination with misoprostol. It can be used in place of mifepristone, which is expensive and unavailable in many countries.[22]

Letrozole is sometimes used as a treatment for gynecomastia, although it is probably most effective at this if caught in an early stage (such as in users of anabolic steroids).[23] [24]

Some studies have shown that letrozole can be used to promote spermatogenesis in male patients with nonobstructive azoospermia.[25]

Letrozole has also been shown to delay the fusing of the growth plates in mice.[26] When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature.[27]

Letrozole has also been used to treat endometriosis.

Endometrial stromal sarcomas are hormonally sensitive tumors as it is represented that letrozole reduces serum estrogen levels. Letrozole is well-tolerated and is a good option for long-term management of this disease.[28] Also in a study on Uterine myoma the volume was successfully reduced by use of an aromatase inhibitor. Rapid onset of action and avoidance of initial gonadotropin flare with an aromatase inhibitor.[29]

Letrozole has been documented to be safe and effective for improving height and pubertal outcomes in children living with constitutional delay in growth and puberty, and is better than testosterone with regard to improvement in testicular volume and delaying bone-age progression. This was documented in a meta-analysis published by Dutta et al. which analyzed data from 7 different randomized controlled trials.[30]

Notes and References

  1. Web site: Femara- letrozole tablet, film coated . DailyMed . 13 May 2022 . 28 August 2022.
  2. Web site: List of nationally authorised medicinal products : Active substance(s): letrozole : Procedure No. PSUSA/00001842/202110. Ema.europa.eu. 30 June 2022.
  3. Web site: Letrozole. 24 January 2003. https://web.archive.org/web/20030124001025/http://www.orgyn.com/resources/genrx/D003330.asp . 30 June 2022. 24 January 2003 .
  4. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 516 .
  5. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  6. Web site: Letrozole - Drug Usage Statistics . ClinCalc . 14 January 2024.
  7. Book: ((World Health Organization)) . The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) . 2023 . 10665/371090 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2023.02 . free .
  8. Drugs.com: for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
  9. Simpson ER . Sources of estrogen and their importance . The Journal of Steroid Biochemistry and Molecular Biology . 86 . 3–5 . 225–30 . September 2003 . 14623515 . 10.1016/S0960-0760(03)00360-1 . 11210435 .
  10. Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B . Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up . The Lancet. Oncology . 12 . 12 . 1101–8 . November 2011 . 22018631 . 3235950 . 10.1016/S1470-2045(11)70270-4 .
  11. Web site: 32nd Annual San Antonio Breast Cancer Symposium . https://web.archive.org/web/20100516171511/http://www.sabcs.org/EnduringMaterials/Index.asp . 16 May 2010 .
  12. The Outcome of 150 Babies Following the Treatment With Letrozole or Letrozole and Gonadotropins . Biljan MM, Hemmings R, Brassard N . 2005 . 10.1016/j.fertnstert.2005.07.230 . 84 . Fertility and Sterility . S95. free .
  13. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, Librach C, Greenblatt E, Casper RF . Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate . Fertility and Sterility . 85 . 6 . 1761–5 . June 2006 . 16650422 . 10.1016/j.fertnstert.2006.03.014 . free .
  14. News: Finally, expert panel bans fertility drug Letrozole. https://web.archive.org/web/20130814052512/http://articles.timesofindia.indiatimes.com/2011-10-18/india/30296687_1_letrozole-breast-cancer-post-menopausal-women. dead. 14 August 2013. 18 October 2011. 14 November 2011. Sinha K . .
  15. News: House panel to govt: Punish those guilty of approving Letrozole . https://web.archive.org/web/20131112050105/http://articles.timesofindia.indiatimes.com/2012-05-09/india/31641343_1_letrozole-anti-cancer-drug-infertility . dead . 12 November 2013 . 10 April 2007 . . 9 May 2012.
  16. Chen DT, Wynia MK, Moloney RM, Alexander GC . U.S. physician knowledge of the FDA-approved indications and evidence base for commonly prescribed drugs: results of a national survey . Pharmacoepidemiology and Drug Safety . 18 . 11 . 1094–100 . November 2009 . 19697444 . 10.1002/pds.1825 . 9779191 . free .
  17. Web site: GMC | Good practice in prescribing medicines – guidance for doctors . Gmc-uk.org . 16 February 2007 . 21 November 2011 . dead . https://web.archive.org/web/20081219225153/http://www.gmc-uk.org/guidance/current/library/prescriptions_faqs.asp#5d . 19 December 2008 .
  18. Zhang J, Zhou K, Shan D, Luo X . Medical methods for first trimester abortion . The Cochrane Database of Systematic Reviews . 5 . CD002855 . May 2022 . 2022 . 10.1002/14651858.CD002855.pub5 . 35608608 . 9128719.
  19. Zhuo Y, Cainuo S, Chen Y, Sun B. The efficacy of letrozole supplementation for medical abortion: a meta-analysis of randomized controlled trials. J Matern Fetal Neonatal Med. 2021 May;34(9):1501-1507. doi: 10.1080/14767058.2019.1638899. Epub 2019 Jul 29. PMID 31257957.
  20. Yeung TW, Lee VC, Ng EH, Ho PC . A pilot study on the use of a 7-day course of letrozole followed by misoprostol for the termination of early pregnancy up to 63 days . Contraception . 86 . 6 . 763–769 . December 2012 . 22717187 . 10.1016/j.contraception.2012.05.009 .
  21. Book: Austria-Codex. Haberfeld H . Österreichischer Apothekerverlag. Vienna. 2009. 2009/2010. 978-3-85200-196-8. de.
  22. Lee VC, Ng EH, Yeung WS, Ho PC . Misoprostol with or without letrozole pretreatment for termination of pregnancy: a randomized controlled trial . Obstetrics and Gynecology . 117 . 2 Pt 1 . 317–23 . February 2011 . 21252745 . 10.1097/AOG.0b013e3182073fbf . 25581158 .
  23. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A . History of aromatase: saga of an important biological mediator and therapeutic target . Endocrine Reviews . 30 . 4 . 343–75 . June 2009 . 19389994 . 10.1210/er.2008-0016 . free .
  24. Web site: https://web.archive.org/web/20100626030758/http://www.gynecomastia-gyno.com/gynecomastia-letrozole-treatment/. Gynecomastia and Letrozole. 26 June 2010. 16 December 2008. GYNECOMASTIA-GYNO.COM. 26 April 2012.
  25. Patry G, Jarvi K, Grober ED, Lo KC . Use of the aromatase inhibitor letrozole to treat male infertility . Fertility and Sterility . 92 . 2 . 829.e1–2 . August 2009 . 19524225 . 10.1016/j.fertnstert.2009.05.014 . free .
  26. Eshet R, Maor G, Ben Ari T, Ben Eliezer M, Gat-Yablonski G, Phillip M . The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice . The Journal of Endocrinology . 182 . 1 . 165–72 . July 2004 . 15225141 . 10.1677/joe.0.1820165 . free .
  27. Zhou P, Shah B, Prasad K, David R . Letrozole significantly improves growth potential in a pubertal boy with growth hormone deficiency . Pediatrics . 115 . 2 . e245-8 . February 2005 . 15653791 . 10.1542/peds.2004-1536 . 36741346 .
  28. Sylvestre VT, Dunton CJ . Treatment of recurrent endometrial stromal sarcoma with letrozole: a case report and literature review . Hormones & Cancer . 1 . 2 . 112–5 . April 2010 . 21761354 . 10.1007/s12672-010-0007-9 . 10358008 . 26057966 . free .
  29. Nothnick WB . The emerging use of aromatase inhibitors for endometriosis treatment . Reproductive Biology and Endocrinology . 9 . 87 . June 2011 . 21693036 . 3135533 . 10.1186/1477-7827-9-87 . free .
  30. Dutta D, Singla R, Surana V, Sharma M . Efficacy and Safety of Letrozole in the Management of Constitutional Delay in Growth and Puberty: A Systematic Review and Meta-analysis. . J Clin Res Pediatr Endocrinol. . September 2021 . 14 . 2 . 131–144 . 34477355 . 10.4274/jcrpe.galenos.2021.2021.0169 . 9176083 . 237400443 .

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