| Revision as of 12:00, 17 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 447430724 of page Exemestane for the Chem/Drugbox validation project (updated: 'DrugBank'). |
Latest revision as of 07:31, 7 December 2024 edit Headbomb (talk | contribs)Edit filter managers, Autopatrolled, Extended confirmed users, Page movers, File movers, New page reviewers, Pending changes reviewers, Rollbackers, Template editors454,511 edits ce |
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{{Short description|Breast cancer medication}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{cs1 config|name-list-style=vanc}}{{Use dmy dates|date=November 2022}} |
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{{Drugbox |
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{{Infobox drug |
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| verifiedrevid = 442628655 |
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| Verifiedfields = changed |
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| IUPAC_name = 6-methylideneandrosta-1,4-diene-3,17-dione<ref>[http://www.ebi.ac.uk/chebi/searchId.do?chebiId=4953 ChEBI_Ref = {{ebicite|correct|EBI}} |
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| Watchedfields = changed |
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| ChEBI exemestane (CHEBI:4953)]</ref> |
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| verifiedrevid = 461098446 |
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| IUPAC_name = 6-Methylideneandrosta-1,4-diene-3,17-dione<ref name="CHeBIID">{{cite web | url = http://www.ebi.ac.uk/chebi/searchId.do?chebiId=4953 | title = Exemestane | work = ] }}</ref> |
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| image = Exemestane.svg |
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| image = Exemestane.svg |
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| width = 225 |
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| image2 = Exemestano.png |
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| image2 = Exemestano.png |
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| width2 = 225 |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| pronounce = {{IPAc-en|ˌ|ɛ|k|s|ə|ˈ|m|ɛ|ˌ|s|t|eɪ|n}}<br />{{respell|EK|sə|ME|stayn}} |
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| tradename = Aromasin |
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| tradename = Aromasin |
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| Drugs.com = {{drugs.com|monograph|exemestane}} |
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| Drugs.com = {{drugs.com|monograph|exemestane}} |
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| MedlinePlus = a607006 |
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| MedlinePlus = a607006 |
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| routes_of_administration = ] |
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| pregnancy_category = D |
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| class = ]; ] |
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| legal_status = Rx only |
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| ATC_prefix = L02 |
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| routes_of_administration = Oral |
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| ATC_suffix = BG06 |
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| legal_UK = POM |
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| legal_UK_comment = <ref>{{cite web | title=Aromasin - Summary of Product Characteristics (SmPC) | website=(emc) | date=16 May 2022 | url=https://www.medicines.org.uk/emc/product/5520 | access-date=29 November 2022}}</ref> |
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| legal_US = Rx only |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = ~60% |
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| bioavailability = ~60%{{Citation needed|date=December 2015}} |
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| protein_bound = 90% |
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| protein_bound = 90% |
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| metabolism = Liver (], ]) |
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| elimination_half-life = 27 hours |
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| elimination_half-life = 24 hours |
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| duration_of_action = 4–5 days{{Citation needed|date=November 2017}} |
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| excretion = Urine and feces ~ 1:1 (mainly metabolites) |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| IUPHAR_ligand = 7073 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 107868-30-4 |
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| CAS_number = 107868-30-4 |
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| ATC_prefix = L02 |
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| ATC_suffix = BG06 |
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| PubChem = 60198 |
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| PubChem = 60198 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D00963 |
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| KEGG = D00963 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = 4953 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 1200374 |
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| ChEMBL = 1200374 |
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| synonyms = FCE-24304 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=20 | H=24 | O=2 |
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| C=20 | H=24 | O=2 |
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| SMILES = O=C\1\C=C/3(C(=C/1)/C(=C)C42CCC(=O)2(CC34)C)C |
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| molecular_weight = 296.403 g/mol |
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| smiles = O=C\1\C=C/3(C(=C/1)/C(=C)C42CCC(=O)2(CC34)C)C |
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| InChI = 1/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1 |
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| InChIKey = BFYIZQONLCFLEV-DAELLWKTBA |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1 |
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| StdInChI = 1S/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1 |
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| StdInChIKey = BFYIZQONLCFLEV-DAELLWKTSA-N |
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| StdInChIKey = BFYIZQONLCFLEV-DAELLWKTSA-N |
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}} |
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'''Exemestane''', sold under the brand name '''Aromasin''' among others, is a ] used to treat ]. It is a member of the class of ]s known as ]s. Some breast cancers require ] to grow. Those cancers have estrogen ] (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. ] is an ] that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers. |
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==Medical uses== |
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Exemestane is ] for the ] treatment of ] women with estrogen-receptor positive early breast cancer who have received two to three years of ] and are switched to it for completion of a total of five consecutive years of adjuvant hormonal therapy.<ref>{{cite journal | vauthors = Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM | display-authors = 6 | title = Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial | journal = Lancet | volume = 369 | issue = 9561 | pages = 559–70 | date = February 2007 | pmid = 17307102 | doi = 10.1016/S0140-6736(07)60200-1 | s2cid = 38977099 }}</ref> |
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US FDA approval was in October 1999.<ref>{{cite web | title = Exemestane Approval Letter | publisher = U.S. Food and Drug Administration | date = 21 October 1999 | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20-753_Aromasin_Approv.pdf }}</ref> |
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Exemestane is also indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.<ref>{{cite web | url = http://www.aromasin.com/content/for_advanced.aspx | title = Aromasin For Advanced Breast Cancer | archive-url = https://web.archive.org/web/20120328103358/http://www.aromasin.com/content/for_advanced.aspx | archive-date=28 March 2012 | work = Aromasin.com }}</ref> |
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For premenopausal women with hormone-receptor–positive breast cancer, adjuvant treatment with ovarian suppression plus the aromatase inhibitor exemestane, as compared with ovarian suppression plus tamoxifen, provides a new treatment option that reduces the risk of recurrence. The TEXT and SOFT trials demonstrated improved disease free survival in patients treated with exemestane and ovarian suppression compared to the tamoxifen and ovarian suppression group. Premenopausal women who receive ovarian suppression may now benefit from an aromatase inhibitor, a class of drugs that until now has been recommended only for postmenopausal women.<ref>{{cite journal | vauthors = Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA | display-authors = 6 | title = Adjuvant exemestane with ovarian suppression in premenopausal breast cancer | journal = The New England Journal of Medicine | volume = 371 | issue = 2 | pages = 107–18 | date = July 2014 | pmid = 24881463 | pmc = 4175521 | doi = 10.1056/NEJMoa1404037 }}</ref> |
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==Contraindications== |
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The drug is contraindicated in ] women, which of course includes pregnant and ] women.<ref name="Austria-Codex" /> |
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==Side effects== |
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The most common side effects (more than 10% of patients) are ]es and sweating, which are typical of estrogen deficiency as caused by exemestane, and also ], headache, and ]. Nausea and ] are mainly observed in patients with advanced breast cancer.<ref name="Austria-Codex" /><ref name="Drugs.com">Drugs.com: {{drugs.com|monograph|exemestane}} on exemestane.</ref> |
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An occasional decrease in lymphocytes has been observed in approximately 20% of patients receiving Aromasin, particularly in patients with pre-existing lymphopenia.<ref>{{Cite web|url=https://www.medicines.org.uk/emc/medicine/2484|title = Aromasin - Summary of Product Characteristics (SMPC) - (Emc)}}</ref> |
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Exemestane has ]ic properties similarly to ] and can produce androgenic side effects such as ] and ], although these are generally associated with supratherapeutic dosages of the drug.<ref name="pmid12404296">{{cite journal | vauthors = Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM | title = An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane | journal = Cancer | volume = 95 | issue = 9 | pages = 2006–16 | date = November 2002 | pmid = 12404296 | doi = 10.1002/cncr.10908 | s2cid = 34798824 | doi-access = free }}</ref> |
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==Overdose== |
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Single doses of up to at least 32-fold (800 mg), as well as continuous therapy with 24-fold (600 mg) the usual daily dose are well tolerated. No life-threatening overdosing is known in humans, but only in animal studies with 2000- to 4000-fold doses (adjusted to ]).<ref name="Austria-Codex" /> |
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== Interactions == |
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Exemestane is metabolized by the liver enzyme ]. While the CYP3A4 inhibitor ] had no significant effect on exemestane levels in a clinical trial, the strong CYP3A4 inductor ] significantly cut exemenstane levels about in half (] −54%, ] −41% for a single dose), potentially compromising its effectiveness. Other 3A4 inductors such as ] and ] are expected to have similar effects.<ref name="Austria-Codex" /><ref name="Drugs.com" /> The clinical relevance of this effect has not been investigated.<ref name="Dinnendahl" /> |
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Estrogens probably reduce exemestane effectiveness:<ref name="Drugs.com" /> It would usually be counter-productive to reduce the body's estrogen synthesis with exemestane and then substitute estrogen with pharmaceuticals. |
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==Pharmacology== |
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===Pharmacodynamics=== |
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Exemestane is an oral steroidal aromatase inhibitor that is used in ER-positive breast cancer in addition to surgery and/or radiation in post-menopausal women. |
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The main source of ] is the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced via the conversion of ]s into estrogen by the aromatase enzyme in the peripheral tissues (i.e. adipose tissue like that of the breast) and a number of sites in the brain. Estrogen is produced locally via the actions of the aromatase enzyme in these peripheral tissues where it acts locally. Any circulating estrogen in post-menopausal women as well as men is the result of estrogen escaping local metabolism and entering the circulatory system.<ref>{{cite journal | vauthors = Simpson ER | title = Sources of estrogen and their importance | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 86 | issue = 3–5 | pages = 225–30 | date = September 2003 | pmid = 14623515 | doi = 10.1016/S0960-0760(03)00360-1 | s2cid = 11210435 }}</ref> |
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Exemestane is an irreversible, steroidal aromatase inactivator of type I, structurally related to the natural substrate ]. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "]." By being structurally similar to enzyme targets, exemestane permanently binds to the enzymes, preventing them from converting androgen into estrogen.<ref name="Austria-Codex">{{cite book|title=Austria-Codex|editor=Jasek, W|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=62nd|isbn=978-3-85200-181-4|pages=656–660|language=German}}</ref> |
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Type II aromatase inhibitors such as ] and ], by contrast, are not steroids and work by interfering with the aromatase's ].<ref name="Dinnendahl">{{cite book|title=Arzneistoff-Profile| veditors = Dinnendahl V, Fricke U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2007|edition=21|volume=4|isbn=978-3-7741-9846-3|language=German}}</ref> |
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A study conducted on young adult males found that the estrogen suppression rate for exemestane varied from 35% for ] (E2) to 70% for ] (E1).<ref> |
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{{cite journal | vauthors = Mauras N, Lima J, Patel D, Rini A, di Salle E, Kwok A, Lippe B | title = Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 12 | pages = 5951–6 | date = December 2003 | pmid = 14671195 | doi = 10.1210/jc.2003-031279 | doi-access = free }}</ref> |
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{{Pharmacodynamics of aromatase inhibitors}} |
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===Pharmacokinetics=== |
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Exemestane is quickly absorbed from the gut, but undergoes a strong ] in the liver. Highest blood plasma concentrations are reached after 1.2 hours in breast cancer patients and after 2.9 hours in healthy subjects. Maximal aromatase inhibition occurs after two to three days.<ref name="Dinnendahl" /> 90% of the absorbed substance are bound to ]s. The liver enzyme CYP3A4 ] the ] group in position 6, and the 17-] group (on the five-membered ring) is reduced by ]s to an ]. Of the resulting metabolites, 40% are excreted via the urine and 40% via the feces within a week. The original substance accounts for only 1% of excretion in the urine. The terminal half-life is 24 hours.<ref name="Austria-Codex" /><ref name="Mutschler">{{Cite book| vauthors = Mutschler E, Schäfer-Korting M |title=Arzneimittelwirkungen |language=German |location=Stuttgart |publisher=Wissenschaftliche Verlagsgesellschaft |year=2001 |edition=8th |page=904 |isbn=3-8047-1763-2}}</ref> |
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==Chemistry== |
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] for comparison]] |
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Exemestane is known chemically as 6-methylideneandrosta-1,4-diene-3,17-dione. Like the aromatase inhibitors ] and ], exemestane is a ] that is structurally similar to 4-androstenedione, the natural substrate of aromatase. It is distinguished from the natural substance only by the methylidene group in position 6 and an additional double bond in position 1.<ref name="Steinhilber">{{cite book|title=Medizinische Chemie| vauthors = Steinhilber D, Schubert-Zsilavecz M, Roth HJ |publisher=Deutscher Apotheker Verlag|location=Stuttgart|year=2005|isbn=3-7692-3483-9|pages=467f|language=German}}</ref> |
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Pure exemestane is a white to off-white powder that is soluble in ] to at least 20 mg/mL. ] <sub>''D''</sub> is +250 to 300° (per g/100 cm<sup>3</sup> and decimetre at 589 ] wavelength).<ref name="Sigma">{{Sigma-Aldrich|Sigma|id=PZ0006|name=Exemestane, ≥ 98% (HPLC)|access-date=12 December 2015}}</ref> |
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==Society and culture== |
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===Performance enhancement=== |
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Exemestane has been used in ] to raise ] (LH) and ] (FSH) levels, which in turn increases the ratio of male over female sexual hormones and so improves performance. The drug also counteracts ] as well as fat and ] following excessive aromatase production due to ] doping.<ref>{{cite book|title=Das Schwarze Buch – Anabole Steroide|year=2007|page=133|isbn=978-3-00-020944-4|language=de| vauthors = Sinner D |publisher=BMS-Verlag }}</ref> It is also used by steroid users to lower female sexual horomone levels following a cycle of steroids, often called a "post-cycle therapy", it is also used alongside ]s in this. |
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Rarely, it is used recreationally by teenagers to delay epiphyseal plate closure and increase adult height, particularly among members of the ] and ] communities, where its use is documented on their forums.<ref>{{cite web | url=https://looksmax.org/threads/ascends-guide-on-how-to-get-hgh-heightmaxxing-teen-manlets-gtfih.904203/ | archive-url=https://web.archive.org/web/20241008222130/https://looksmax.org/threads/ascends-guide-on-how-to-get-hgh-heightmaxxing-teen-manlets-gtfih.904203/ | archive-date=8 October 2024 | title=Ascend's Guide on how to get HGH/Heightmaxxing!!!!!! (Teen manlets gtfih) | date=19 December 2023 }}</ref><ref>{{cite journal | pmc=3143915 | date=2011 | title=Aromatase inhibitors in men: Effects and therapeutic options | journal=Reproductive Biology and Endocrinology | volume=9 | page=93 | doi=10.1186/1477-7827-9-93 | doi-access=free | pmid=21693046 | vauthors = De Ronde W, De Jong FH }}</ref> However, its effectiveness for this purpose is debatable. |
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Along with other aromatase inhibitors, exemestane is on the ]'s list of prohibited substances.<ref>{{cite web | url = http://www.karatecanada.org/docs/medical/CCES-PUB-SubstanceClassification-E.pdf | title = Substance Classification Booklet, Version 4.0 | archive-url = https://web.archive.org/web/20130927141936/http://www.karatecanada.org/docs/medical/CCES-PUB-SubstanceClassification-E.pdf | archive-date=27 September 2013 | work = Canadian Centre for Ethics in Sport | date = January 2009 }}</ref> |
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==Research== |
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Oral exemestane 25 mg/day for 2–3 years of adjuvant therapy was generally more effective than 5 years of continuous adjuvant ] in the treatment of postmenopausal women with early-stage estrogen receptor-positive/unknown receptor status breast in a large well-designed{{citation needed|date=December 2015}} trial. Preliminary data from the open-label TEAM trial comparing exemestane with tamoxifen indicated in 2009 that exemestane 25 mg/day is also effective in the primary adjuvant treatment of early-stage breast cancer in postmenopausal women.<ref name="exem">{{cite journal | vauthors = Deeks ED, Scott LJ | title = Exemestane: a review of its use in postmenopausal women with breast cancer | journal = Drugs | volume = 69 | issue = 7 | pages = 889–918 | year = 2009 | pmid = 19441873 | doi = 10.2165/00003495-200969070-00007 | s2cid = 249879736 | url = http://adisonline.com/drugs/Abstract/2009/69070/Exemestane__A_Review_of_its_Use_in_Postmenopausal.7.aspx | access-date = 29 March 2010 | archive-url = https://web.archive.org/web/20111008153710/http://adisonline.com/drugs/Abstract/2009/69070/Exemestane__A_Review_of_its_Use_in_Postmenopausal.7.aspx | archive-date = 8 October 2011 | url-status = dead }}</ref> |
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Interim phase III trial results in 2011 showed that adding ] to exemestane therapy against advanced breast cancer can significantly improve ] compared with exemestane therapy alone.<ref>{{cite news |url=http://www.genengnews.com/gen-news-highlights/positive-trial-data-leads-novartis-to-plan-breast-cancer-filing-for-afinitor-by-year-end/81245384/ |title=Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End |year=2011 }}</ref><ref>{{cite news |url=https://www.melanotanexpress.com/product/exemestane-aromasin-25mg-per-ml-30-ml-bottle/ |title=Exemestane 25 mg |website=www.melanotanexpress.com }}</ref> |
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A Phase III trial was reported in 2011, concluding that the use of exemestane in postmenopausal women at an increased risk for breast cancer reduced the incidence of invasive breast cancer. In 4,560 women, after 35 months, the administration of exemestane at a dose of 25 mg/day resulted in a 65% reduction in the risk of breast cancer compared with placebo; annual incidence rates were 0.19% and 0.55%, respectively (hazard ratio: 0.35; 95% CI ; p = 0.002).<ref>{{cite web| vauthors = Goss PE |title=Exemestane Offers New Option for Breast Cancer Prevention|url=http://chicago2011.asco.org/ASCODailyNews/HER2.aspx|date=6 June 2011|access-date=6 June 2011|publisher=American Society of Clinical Oncology|url-status=dead|archive-url=https://web.archive.org/web/20110711004716/http://chicago2011.asco.org/ASCODailyNews/HER2.aspx|archive-date=11 July 2011}}</ref> |
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== References == |
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{{Reflist|35em}} |
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== External links == |
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{{Estrogens and antiestrogens}} |
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{{Androgen receptor modulators}} |
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