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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/11 02:38:04」(JST)

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

Uses

FDA-approved use

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

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

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

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

Adverse effects

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

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

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]

References

^ ^a ^b ^c 003330 Letrozole
^ ^a ^b Drugs.com: monograph for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
^ 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.
^ Sinha, Kounteya (18 October 2011). "Finally, expert panel bans fertility drug Letrozole". The Times of India. Retrieved 14 November 2011.
^ "House panel to govt: Punish those guilty of approving Letrozole". The Times of India. 10 April 2007. Retrieved 9 May 2012.
^ 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.
^ "GMC | Good practice in prescribing medicines – guidance for doctors". Gmc-uk.org. 16 February 2007. Retrieved 21 November 2011.
^ 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.
^ 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.
^ "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.
^ 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.
^ 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" (PDF). Journal of Endocrinology 182 (1): 165–172. doi:10.1677/joe.0.1820165. PMID 15225141.
^ 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.
^ Endometriosis ESHRE abstract
^ ^a ^b ^c Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
^ 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.
^ 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
^ 32nd Annual San Antonio Breast Cancer Symposium

External links

Femara website

UpToDate Contents

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1. レトロゾールによる排卵誘発 ovulation induction with letrozole
2. 転移性ホルモン受容体陽性乳癌に対する治療アプローチ：内分泌療法 treatment approach to metastatic hormone receptor positive breast cancer endocrine therapy
3. 排卵誘発の概要 overview of ovulation induction
4. アロマターゼ阻害剤による骨量減少の評価およびマネージメント evaluation and management of aromatase inhibitor induced bone loss
5. 非転移性ホルモン受容体陽性乳癌に対する補助内分泌療法 adjuvant endocrine therapy for non metastatic hormone receptor positive breast cancer

English Journal

Dual targeting of TNF-α and free radical toxic stress as a promising strategy to manage experimental polycystic ovary.

Rezvanfar MA1,2, Saeedi S3, Mansoori P3, Saadat S3, Goosheh M4, Shojaei Saadi HA5, Baeeri M2, Abdollahi M1,2.
Pharmaceutical biology.Pharm Biol.2016 Jan;54(1):80-90. doi: 10.3109/13880209.2015.1014922. Epub 2015 May 8.
CONTEXT: It is now clear that oxidative stress (OS) and chronic low-grade inflammation are two main pathways involved in polycystic ovary syndrome (PCOS) pathogenesis. Therefore, simultaneous targeting of these pathways by means of carvedilol and Semelil (ANGIPARS™), as established medicines with
PMID 25955958

The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence.

Ignatiadis M1, Azim HA Jr2, Desmedt C2, Veys I3, Larsimont D4, Salgado R2, Lyng MB5, Viale G6, Leyland-Jones B7, Giobbie-Hurder A8, Kammler R9, Dell'Orto P6, Rothé F2, Laïos I4, Ditzel HJ10, Regan MM8, Piccart M11, Michiels S12, Sotiriou C1.
JAMA oncology.JAMA Oncol.2015 Dec 3:1-8. doi: 10.1001/jamaoncol.2015.4377. [Epub ahead of print]
Importance: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was devel
PMID 26633571

Treatment strategies for the infertile polycystic ovary syndrome patient.

Tannus S1, Burke YZ1, Kol S1.
Women's health (London, England).Womens Health (Lond Engl).2015 Dec 2. [Epub ahead of print]
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Infertility is a prevalent presenting feature of PCOS, and approximately 75% of these women suffer infertility due to anovulation. Life style modification is considered the first-line treatment and i
PMID 26626234

Japanese Journal

レトロゾールによる内分泌療法が有効であった91歳男性乳癌の1例

中田琢巳,森川あけみ,杉山保幸,山田鉄也
日本臨床外科学会雑誌 75(4), 906-910, 2014
症例は91歳，男性．併存症として，閉塞性動脈硬化症・狭心症・2型糖尿病・高血圧症などがあり，当院内科での治療中に左乳頭下に3.5cmの腫瘤を自覚するようになり当科を受診した．男性乳癌と診断されたが初期治療としては合併症を考慮してレトロゾール内服による内分泌療法が選択された．投与開始後から腫瘍の縮小が認められ，約6カ月間で腫瘤は1.7cmまでの縮小を認め，自覚症状は著明に改善した．症例の少なさから女 …
NAID 130004713878

2) インスリン抵抗性を持つ多嚢胞性卵巣症候群患者の診断とメトホルミン療法の適応の検討(シンポジウム3:生殖「多嚢胞性卵巣症候群(PCOS)の病因・病態と管理」,第65回日本産科婦人科学会・学術講演会)

松崎利也
日本産科婦人科學會雜誌 65(12), 2698-2708, 2013-12-01
… Letrozole-indused PCOS model rats were used to analyze hypothalamic kisspeptin mRNA expression. …
NAID 110009685695

Positive Therapeutic Response to Bevacizumab Plus Paclitaxel in a Patient with Advanced, Life-Threatening Breast Cancer and Carcinomatous Lymphangitis:a Subsequent Treatment Change to Hormone Therapy

Ishizuna Kazuo,Ninomiya Jun,Kojima Makoto,Kawashima Miho,Nishibayashi Fumiko,Nozaki Miwako,Yamagishi Hidetsugu,Ueda Yoshihiko,Oya Masatoshi
Dokkyo journal of medical sciences 40(2), 113-117, 2013-07-25
… Thus, bevacizumab plus paclitaxelwere discontinued and the treatment was changed to oral letrozole (2.5 mg/day). …
NAID 110009606623

Related Pictures

★リンクテーブル★

リンク元	「レトロゾール」「Femara」

「レトロゾール」

Letrozole
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; category	US: D (Evidence of risk);
Legal status	CA: Schedule VII; UK: Prescription-only (POM); US: ℞-only;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	99.9%
Protein binding	60%, mainly to albumin
Metabolism	pharmacologically-inactive carbinol metabolite (4,4΄-methanol-bisbenzonitrile)
Biological half-life	2 days
Excretion	Kidneys
Identifiers
CAS Registry Number	112809-51-5
ATC code	L02BG04
PubChem	CID: 3902
IUPHAR/BPS	5209
DrugBank	DB01006
ChemSpider	3765
UNII	7LKK855W8I
KEGG	D00964
ChEBI	CHEBI:6413
ChEMBL	CHEMBL1444
Chemical data
Formula	C17H11N5
Molecular mass	285.303 g/mol
	SMILES N#Cc1ccc(cc1)C(c2ccc(C#N)cc2)n3ncnc3 ;
	InChI 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 ; Key:HPJKCIUCZWXJDR-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

英: letrozole
関: フェマーラ Femara

「Femara」

　　[★]

フェマーラ

関: letrozole

[Letrozole-1] 003330 Letrozole

[FDA-2] 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.

[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" (PDF). 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

[AustriaCodex-15] 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

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letrozole