Letrozole

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Letrozole
Letrozole2DACS.svg
Letrozol3D.png
Systematic (IUPAC) name
4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile
Clinical data
Trade names Femara
AHFS/Drugs.com monograph
MedlinePlus a698004
Licence data US FDA:link
Pregnancy cat. D (US)
Legal status Schedule VII (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 99.9%
Protein binding 60%, mainly to albumin
Metabolism pharmacologically-inactive carbinol metabolite (4,4΄-methanol-bisbenzonitrile)[1]
Half-life 2 days[1]
Excretion Kidneys[1]
Identifiers
CAS number 112809-51-5 YesY
ATC code L02BG04
PubChem CID 3902
DrugBank DB01006
ChemSpider 3765 YesY
UNII 7LKK855W8I YesY
KEGG D00964 YesY
ChEBI CHEBI:6413 YesY
ChEMBL CHEMBL1444 YesY
Chemical data
Formula C17H11N5 
Mol. mass 285.303 g/mol
 YesY (what is this?)  (verify)

Letrozole (INN, trade name Femara) is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery.

Uses[edit]

FDA-approved use[edit]

Femara 2.5 mg oral tablet

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.[2]

Off-label uses[edit]

Letrozole has been used for ovarian stimulation by fertility doctors since 2001 because it has fewer side-effects than clomiphene (Clomid) and less chance of multiple gestation. A Canadian study presented at the American Society of Reproductive Medicine 2005 Conference suggested that letrozole may increase the risk of birth defects.[citation needed] A more detailed ovulation induction follow-up study found that letrozole, compared with a control group of clomiphene, had significantly lower congenital malformations and chromosomal abnormalities at an overall rate of 2.4% (1.2% major malformations) compared with clomiphene 4.8% (3.0% major malformations).[3] Despite this, India banned the usage of letrozole in 2011, citing potential risks to infants.[4] 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;[5] however, such off-label uses are legal in many countries such as the US and UK.[6][7]

The anti-estrogen 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.[8]

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).[9][10][unreliable source?]

Some studies have shown that letrozole can be used to promote spermatogenesis in male patients suffering from nonobstructive azoospermia.[11]

Letrozole has also been shown to delay the fusing of the growth plates in mice.[12] When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature.[13]

Letrozole has also been used to treat endometriosis.[14]

Mechanism of action[edit]

Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.

Letrozole prevents the 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 mineralo- or corticosteroids.

Contraindications[edit]

Letrozole is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation.[15]

Adverse effects[edit]

The most common side effects are sweating, hot flashes, arthralgia (joint pain), and fatigue.[15]

Generally, side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis,[2] which is in certain patient populations such as post-menopausal women or osteoporotics, bisphosphonates may also be prescribed.[citation needed]

Interactions[edit]

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.[15]

Comparison with tamoxifen[edit]

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.[16] 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.[17][18]

Synthesis[edit]

Letrozole can by synthesized from 4-cyanobenzyl bromide, triazole, and 4-fluorobenzonitrile:[19] Letrozole.png

See also[edit]

References[edit]

  1. ^ a b c 003330 Letrozole
  2. ^ a b Drugs.com: monograph for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
  3. ^ Tulandi T, Martin J, Al-Fadhli R, et al. (June 2006). "Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate". Fertility and Sterility 85 (6): 1761–5. doi:10.1016/j.fertnstert.2006.03.014. PMID 16650422. 
  4. ^ Sinha, Kounteya (18 October 2011). "Finally, expert panel bans fertility drug Letrozole". The Times of India. Retrieved 14 November 2011. 
  5. ^ "House panel to govt: Punish those guilty of approving Letrozole". The Times of India. 10 April 2007. Retrieved 9 May 2012. 
  6. ^ Chen DT, Wynia MK, Moloney RM, Alexander GC (2009). "Physician knowledge of the FDA-approved indications of commonly prescribed drugs: results of a national survey". Pharmacoepidemiology and Drug Safety 18 (11): 1–7. doi:10.1002/pds.1825. PMID 19697444. 
  7. ^ "GMC | Good practice in prescribing medicines – guidance for doctors". Gmc-uk.org. 16 February 2007. Retrieved 21 November 2011. 
  8. ^ Vivian Chi Yan Lee, Ernest Hung Yu Ng, William Shu Biu Yeung, Pak Chung Ho (2011). "Misoprostol With or Without Letrozole Pretreatment for Termination of Pregnancy". Ob Gyn. 117 (2, Part 1): 317–323. doi:10.1097/AOG.0b013e3182073fbf. 
  9. ^ Santen, R. J.; Brodie, H.; Simpson, E. R.; Siiteri, P. K.; Brodie, A. (2009). "History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target". Endocrine Reviews 30 (4): 343–375. doi:10.1210/er.2008-0016. PMID 19389994.  edit
  10. ^ "Gynecomastia and Letrozole". GYNECOMASTIA-GYNO.COM: ...a resource for gynecomastia sufferers... 16 December 2008. Archived from the original on 26 June 2010. Retrieved 26 April 2012. 
  11. ^ Geneviève Patry, Keith Jarvi, Ethan D. Grober, Kirk C. Lo (August 2009). "Use of the aromatase inhibitor letrozole to treat male infertility". Fertility and Sterility 92 (2): 829.e1–829.e2. doi:10.1016/j.fertnstert.2009.05.014. 
  12. ^ R Eshet, G Maor, T Ben Ari, M Ben Eliezer, G Gat-Yablonski, M Phillip (2004). "The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice". Journal of Endocrinology 182 (1): 165–172. doi:10.1677/joe.0.1820165. PMID 15225141. 
  13. ^ Ping Zhou MD, Bina Shah MD, Kris Prasad PhD, Raphael David MD (2005). "Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency". Journal of the American Academy of Pediatrics 115 (2): 245–248. doi:10.1542/peds.2004-1536. PMID 15653791. 
  14. ^ Endometriosis ESHRE abstract
  15. ^ a b c Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. 
  16. ^ Simpson ER (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. 
  17. ^ Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer, the BIG 1–98 Collaborative Group, N Engl J Med, 361:766, 2009 Aug 20
  18. ^ 32nd Annual San Antonio Breast Cancer Symposium
  19. ^ Lang, M; Batzl, C; Furet, P; Bowman, R; Hausler, A; Bhatnagar, A (1993). "Structure-activity relationships and binding model of novel aromatase inhibitors". The Journal of Steroid Biochemistry and Molecular Biology 44 (4–6): 421–8. doi:10.1016/0960-0760(93)90245-R. PMID 8476755. 

External links[edit]