Letrozole

Last updated

Letrozole
Letrozole.svg
Letrozol3D.png
Clinical data
Trade names Femara, others
AHFS/Drugs.com Monograph
MedlinePlus a698004
License data
Routes of
administration 		By mouth
Drug class Aromatase inhibitor; Antiestrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 99.9%
Protein binding 60%, mainly to albumin
Metabolism pharmacologically-inactive metabolites Bis(4-cyanophenyl)methanol and 4,4'-dicyanobenzophenone. [3]
Elimination half-life 2 days [3]
Excretion Kidney [3]
Identifiers
  • 4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.200.357 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H11N5
Molar mass 285.310 g·mol−1
3D model (JSmol)
  • N#Cc1ccc(cc1)C(c2ccc(C#N)cc2)n3ncnc3
  • InChI=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 Yes check.svgY
  • Key:HPJKCIUCZWXJDR-UHFFFAOYSA-N Yes check.svgY
   (verify)

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer for post-menopausal women. [1]

Contents

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 1 million prescriptions. [5] [6] It is on the World Health Organization's List of Essential Medicines. [7]

Medical uses

Breast cancer

Femara 2.5 mg oral tablet 000549lg Femara.jpg
Femara 2.5 mg oral tablet

Letrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer; [1] extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy; [1] first and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer. [1]

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 is recommended as the first-line medication for ovulation induction in polycystic ovary syndrome. Compared to clomiphene (Clomid), it causes higher number of ovulation and live birth rates. It has the same rate of multiple pregnancies (such as twins), [12] and the same rate of miscarriages. [13] The use of letrozole is typically off-label, and some countries may not allow its prescription. [12]

India banned the usage of letrozole in 2011, citing potential risks to infants [14] while in 2012, an Indian parliamentary committee said that their office of the drug controller had colluded with letrozole's makers to approve the drug for infertility in India. The committee also stated that letrozole's use for infertility was illegal worldwide. [15]

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. [16] [17] [18]

Use in sports

Letrozole is considered a performance enhancing drug by the World Antidoping Agency (WADA), as are other aromatase inhibitors, because it may be used to counteract the side effects of anabolic steroids. Letrozole itself is not evidenced as being a performance enhancer. [19]

Contraindications

Letrozole is contraindicated in women having a pre-menopausal hormonal status. Precautions are advised against becoming pregnant while using letrozole; on the loss of bone mineral density; on the increased level of cholesterol and fat in the blood; and on dizziness and against driving. [20] Breast feeding (lactation) is also counterindicated. [21]

Side effects

The most common side effects are sweating, hot flushes, arthralgia (joint pain), and fatigue. [21]

Generally, side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, [22] which is why in certain patient populations such as post-menopausal women or osteoporotics, bisphosphonates may also be prescribed.[ citation needed ]

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. [21]

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.[ citation needed ]

Pharmacodynamics of aromatase inhibitors
GenerationMedicationDosage% inhibitionaClassbIC50c
First Testolactone 250 mg 4x/day p.o.?Type I?
100 mg 3x/week i.m.?
Rogletimide 200 mg 2x/day p.o.
400 mg 2x/day p.o.
800 mg 2x/day p.o.		50.6%
63.5%
73.8%		Type II?
Aminoglutethimide 250 mg mg 4x/day p.o.90.6%Type II4,500 nM
Second Formestane 125 mg 1x/day p.o.
125 mg 2x/day p.o.
250 mg 1x/day p.o.		72.3%
70.0%
57.3%		Type I30 nM
250 mg 1x/2 weeks i.m.
500 mg 1x/2 weeks i.m.
500 mg 1x/1 week i.m.		84.8%
91.9%
92.5%
Fadrozole 1 mg 1x/day p.o.
2 mg 2x/day p.o.		82.4%
92.6%		Type II?
Third Exemestane 25 mg 1x/day p.o.97.9%Type I15 nM
Anastrozole 1 mg 1x/day p.o.
10 mg 1x/day p.o.		96.7–97.3%
98.1%		Type II10 nM
Letrozole0.5 mg 1x/day p.o.
2.5 mg 1x/day p.o.		98.4%
98.9%–>99.1%		Type II2.5 nM
Footnotes:a = In postmenopausal women. b = Type I: Steroidal, irreversible (substrate-binding site). Type II: Nonsteroidal, reversible (binding to and interference with the cytochrome P450 heme moiety). c = In breast cancer homogenates. Sources: See template.

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. [23]

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). [24] [25] [ unreliable source? ]

Some studies have shown that letrozole can be used to promote spermatogenesis in male patients with nonobstructive azoospermia. [26]

Letrozole has also been shown to delay the fusing of the growth plates in mice. [27] When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature. [28]

Letrozole has also been used to treat endometriosis. [29]

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. [30] 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. [31]

References

  1. 1 2 3 4 5 "Femara- letrozole tablet, film coated". DailyMed. 13 May 2022. Retrieved 28 August 2022.
  2. ↑ "List of nationally authorised medicinal products : Active substance(s): letrozole : Procedure No. PSUSA/00001842/202110" (PDF). Ema.europa.eu. Retrieved 30 June 2022.
  3. 1 2 3 "Letrozole". 24 January 2003. Archived from the original on 24 January 2003. Retrieved 30 June 2022.
  4. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 516. ISBN   9783527607495.
  5. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  6. ↑ "Letrozole - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  7. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  8. ↑ "Letrozole Monograph for Professionals". Drugs.com. 25 May 2023. Retrieved 26 December 2024.
  9. ↑ Simpson ER (September 2003). "Sources of estrogen and their importance". The Journal of Steroid Biochemistry and Molecular Biology. 86 (3–5): 225–30. doi:10.1016/S0960-0760(03)00360-1. PMID   14623515. S2CID   11210435.
  10. ↑ Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, et al. (November 2011). "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. doi:10.1016/S1470-2045(11)70270-4. PMC   3235950 . PMID   22018631.
  11. ↑ "32nd Annual San Antonio Breast Cancer Symposium". Archived from the original on 16 May 2010.
  12. 1 2 Teede HJ, Tay CT, Laven JJ, Dokras A, Moran LJ, Piltonen TT, et al. (2023). International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2023 (PDF). Melbourne, Australia: Monash University. pp. 145–146. ISBN   978-0-6458209-0-4.
  13. ↑ Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C (2022). "Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome". Cochrane Database of Systematic Reviews (9). doi:10.1002/14651858.cd010287.pub4/full. ISSN   1465-1858. Archived from the original on 10 February 2024.
  14. ↑ Sinha K (18 October 2011). "Finally, expert panel bans fertility drug Letrozole". The Times of India . Archived from the original on 14 August 2013. Retrieved 14 November 2011.
  15. ↑ "House panel to govt: Punish those guilty of approving Letrozole". The Times of India . 10 April 2007. Archived from the original on 12 November 2013. Retrieved 9 May 2012.
  16. ↑ Zhang J, Zhou K, Shan D, Luo X (May 2022). "Medical methods for first trimester abortion". The Cochrane Database of Systematic Reviews. 2022 (5): CD002855. doi:10.1002/14651858.CD002855.pub5. PMC   9128719 . PMID   35608608.{{cite journal}}: CS1 maint: article number as page number (link)
  17. ↑ 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.
  18. ↑ Yeung TW, Lee VC, Ng EH, Ho PC (December 2012). "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. doi:10.1016/j.contraception.2012.05.009. PMID   22717187.
  19. ↑ "USADA Letrozole". April 2021. Retrieved 11 November 2024.
  20. ↑ Mayo Clinic, "Letrozole (oral route)", https://www.mayoclinic.org/drugs-supplements/letrozole-oral-route/description/drg-20067579
  21. 1 2 3 Haberfeld H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN   978-3-85200-196-8.
  22. ↑ Drugs.com: Monograph for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
  23. ↑ Lee VC, Ng EH, Yeung WS, Ho PC (February 2011). "Misoprostol with or without letrozole pretreatment for termination of pregnancy: a randomized controlled trial". Obstetrics and Gynecology. 117 (2 Pt 1): 317–23. doi:10.1097/AOG.0b013e3182073fbf. PMID   21252745. S2CID   25581158.
  24. ↑ Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A (June 2009). "History of aromatase: saga of an important biological mediator and therapeutic target". Endocrine Reviews. 30 (4): 343–75. doi: 10.1210/er.2008-0016 . PMID   19389994.
  25. ↑ "Gynecomastia and Letrozole". GYNECOMASTIA-GYNO.COM. 16 December 2008. Archived from the original on 26 June 2010. Retrieved 26 April 2012.
  26. ↑ Patry G, Jarvi K, Grober ED, Lo KC (August 2009). "Use of the aromatase inhibitor letrozole to treat male infertility". Fertility and Sterility. 92 (2): 829.e1–2. doi: 10.1016/j.fertnstert.2009.05.014 . PMID   19524225.
  27. ↑ Eshet R, Maor G, Ben Ari T, Ben Eliezer M, Gat-Yablonski G, Phillip M (July 2004). "The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice". The Journal of Endocrinology. 182 (1): 165–72. doi: 10.1677/joe.0.1820165 . PMID   15225141.
  28. ↑ Zhou P, Shah B, Prasad K, David R (February 2005). "Letrozole significantly improves growth potential in a pubertal boy with growth hormone deficiency" . Pediatrics. 115 (2): e245-8. doi:10.1542/peds.2004-1536. PMID   15653791. S2CID   36741346.
  29. 1 2 Nothnick WB (June 2011). "The emerging use of aromatase inhibitors for endometriosis treatment". Reproductive Biology and Endocrinology. 9: 87. doi: 10.1186/1477-7827-9-87 . PMC   3135533 . PMID   21693036.
  30. ↑ Sylvestre VT, Dunton CJ (April 2010). "Treatment of recurrent endometrial stromal sarcoma with letrozole: a case report and literature review". Hormones & Cancer. 1 (2): 112–5. doi: 10.1007/s12672-010-0007-9 . PMC   10358008 . PMID   21761354. S2CID   26057966.
  31. ↑ Dutta D, Singla R, Surana V, Sharma M (September 2021). "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. 14 (2): 131–144. doi:10.4274/jcrpe.galenos.2021.2021.0169. PMC   9176083 . PMID   34477355. S2CID   237400443.
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