Letrozole

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor which is used in the treatment of hormonally-responsive breast cancer after surgery.

Letrozole
Clinical data
Trade namesFemara, others
AHFS/Drugs.comMonograph
MedlinePlusa698004
License data
Routes of
administration		By mouth (tablets)
Drug classAromatase inhibitor; Antiestrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability99.9%
Protein binding60%, mainly to albumin
Metabolismpharmacologically-inactive metabolites Bis(4-cyanophenyl)methanol and 4,4'-dicyanobenzophenone.[1]
Elimination half-life2 days[1]
ExcretionKidneys[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.200.357
Chemical and physical data
FormulaC17H11N5
Molar mass285.310 g·mol−1
3D model (JSmol)
  (verify)

It was patented in 1986 and approved for medical use in 1996.[2]

Medical uses

Breast cancer
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.[3]

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.[4] 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.[5][6]

Ovulation induction
Further information: 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 letrozole 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.[7] A larger, follow-up study with 911 babies compared those born following treatment with letrozole to those born following treatment with clomiphene.[8] 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.[9] 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;[10] however, such off-label uses are legal in many countries such as the US and UK.[11][12]

Other uses

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.[13]

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).[14][15]

Some studies have shown that letrozole can be used to promote spermatogenesis in male patients suffering from nonobstructive azoospermia.[16]

Letrozole has also been shown to delay the fusing of the growth plates in mice.[17] When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature.[18]

Letrozole has also been used to treat endometriosis.[19]

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.[20] 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.[19]

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 flashes, 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,[3] which is 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.[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.

Pharmacodynamics of aromatase inhibitors
GenerationMedicationDosage% inhibitionaClassbIC50c
FirstTestolactone250 mg 4x/day p.o.?Type I?
100 mg 3x/week i.m.?
Rogletimide200 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?
Aminoglutethimide250 mg mg 4x/day p.o.90.6%Type II4,500 nM
SecondFormestane125 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%
Fadrozole1 mg 1x/day p.o.
2 mg 2x/day p.o.		82.4%
92.6%		Type II?
ThirdExemestane25 mg 1x/day p.o.97.9%Type I15 nM
Anastrozole1 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.

References
  1. 003330 Letrozole
  2. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 516. ISBN 9783527607495.
  3. Drugs.com: Monograph for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
  4. 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.
  5. 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 (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.
  6. "32nd Annual San Antonio Breast Cancer Symposium". Archived from the original on 2010-05-16.
  7. Biljan MM, Hemmings R, Brassard N (2005). "The Outcome of 150 Babies Following the Treatment With Letrozole or Letrozole and Gonadotropins". Fertility and Sterility. 84: S95. doi:10.1016/j.fertnstert.2005.07.230.
  8. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, 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.
  9. Sinha K (18 October 2011). "Finally, expert panel bans fertility drug Letrozole". The Times of India. Retrieved 14 November 2011.
  10. "House panel to govt: Punish those guilty of approving Letrozole". The Times of India. 10 April 2007. Retrieved 9 May 2012.
  11. Chen DT, Wynia MK, Moloney RM, Alexander GC (November 2009). "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. doi:10.1002/pds.1825. PMID 19697444. S2CID 9779191.
  12. "GMC | Good practice in prescribing medicines – guidance for doctors". Gmc-uk.org. 16 February 2007. Archived from the original on 19 December 2008. Retrieved 21 November 2011.
  13. 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.
  14. 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.
  15. "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.
  16. 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.
  17. 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" (PDF). The Journal of Endocrinology. 182 (1): 165–72. doi:10.1677/joe.0.1820165. PMID 15225141. Archived from the original (PDF) on 2009-10-07. Retrieved 2010-01-20.
  18. 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.
  19. 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.
  20. 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. PMID 21761354. S2CID 26057966.
  21. Haberfeld H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 978-3-85200-196-8.
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