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. [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 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.[ citation needed ] 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. [21]

Generally, side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, [8] 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. [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] [ unreliable source? ]

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. [28]

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. [29] 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. [28]

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]

Related Research Articles

<span class="mw-page-title-main">Anastrozole</span> Chemical compound

Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk. It is taken by mouth.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

<span class="mw-page-title-main">Clomifene</span> Infertility treatment for women

Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course of treatment that usually lasts for five days.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Aromatase inhibitor</span> Class of drugs

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.

<span class="mw-page-title-main">Exemestane</span> Breast cancer medication

Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.

Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.

Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.

<span class="mw-page-title-main">Testolactone</span> Chemical compound

Testolactone is a non-selective, irreversible, steroidal aromatase inhibitor which is used as an antineoplastic drug to treat advanced-stage breast cancer. The drug was discontinued in 2008 and is no longer available for medical use.

Antihormone therapy is a type of hormone therapy that suppresses selected hormones or their effects, in contrast with hormone replacement therapy, which encourages hormone activity.

Infertility in polycystic ovary disease (PCOS) is a hormonal imbalance in women that is thought to be one of the leading causes of female infertility. Polycystic ovary syndrome causes more than 75% of cases of anovulatory infertility.

<span class="mw-page-title-main">Gynecomastia</span> Endocrine system disorder of human male breast

Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Gynecomastia can cause significant psychological distress or unease.

Kathleen I. Pritchard, is the head of oncology at Sunnybrook Health Sciences Centre in Toronto, Canada, specializing in breast cancer therapies, and leading the clinical trials division of the centre. She has authored numerous studies on women's health, breast cancer, hormone replacement therapy, public health, and research methodology. According to Thomson Reuters, Pritchard was one of the most cited researchers in the world in 2014 and 2015.

<span class="mw-page-title-main">Progonadotropin</span> Drug class

A progonadotropin, or hypergonadotropin, also known as a gonad stimulant, is a type of drug which increases the secretion of one or both of the major gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This, in turn, results in increased function and maintenance of the gonads and increased gonadal steroidogenesis of sex hormones such as androgens, estrogens, and progestogens. Progonadotropins are the functional opposites of antigonadotropins. They have clinical applications in the treatment of hypogonadism and infertility. Conversely, hypergonadotropic effects can occur as a side effect of some drugs. Examples of progonadotropic drugs include gonadotropin-releasing hormone (GnRH) agonists when administered in a pulsatile manner, antiestrogens such as tamoxifen, clomifene, fulvestrant, and aromatase inhibitors like anastrozole, and, only in men, pure antiandrogens such as flutamide, bicalutamide, enzalutamide, and apalutamide.

Estrogen deprivation therapy, also known as endocrine therapy, is a form of hormone therapy that is used in the treatment of breast cancer. Modalities include antiestrogens or estrogen blockers such as selective estrogen receptor modulators (SERMs) like tamoxifen, selective estrogen receptor degraders like fulvestrant, and aromatase inhibitors like anastrozole and ovariectomy.

<span class="mw-page-title-main">Triphenylchloroethylene</span> Synthetic form of estrogen

Triphenylchloroethylene, or triphenylchlorethylene, also known as chlorotriphenylethylene or as phenylstilbene chloride, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s for the treatment of menopausal symptoms, vaginal atrophy, lactation suppression, and all other estrogen-indicated conditions.

<span class="mw-page-title-main">Non steroidal aromatase inhibitors</span>

Non-Steroidal Aromatase Inhibitors (NSAIs) are one of two categories of aromatase inhibitors (AIs). AIs are divided into two categories, steroidal aromatase inhibitors and non-steroidal aromatase inhibitors that is based on their mechanism of action and structure. NSAIs are mainly used to treat breast cancer in women. NSAIs binding is a reversible process where NSAIs binds to the aromatase enzyme through non-covalent interactions. When aromatase inhibitors (AIs) are used to treat breast cancer the main target is the aromatase enzyme which is responsible for the high estrogen level.

References

  1. 1 2 "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. 1 2 Drugs.com: Monograph for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
  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, 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.
  11. ↑ "32nd Annual San Antonio Breast Cancer Symposium". Archived from the original on 16 May 2010.
  12. ↑ 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 .
  13. ↑ 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.
  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. ↑ 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.
  17. ↑ "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.
  18. ↑ 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.
  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, Tracy Wing Yee; Lee, Vivian Chi Yan; Ng, Ernest Hung Yu; Ho, Pak Chung (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.
  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. ↑ 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.
  23. ↑ 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.
  24. ↑ "Gynecomastia and Letrozole". GYNECOMASTIA-GYNO.COM. 16 December 2008. Archived from the original on 26 June 2010. Retrieved 26 April 2012.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. 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.
  29. ↑ 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.
  30. ↑ 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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