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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields =
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<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability = 63%<ref name="Lello2010">{{cite journal|last1=Lello|first1=Stefano|title=Nomegestrol Acetate|journal=Drugs|volume=70|issue=5|year=2010|pages=541–559|issn=0012-6667|doi=10.2165/11532130-000000000-00000|pmid=20329803}}</ref>
| bioavailability = 63%<ref name="Lello2010">{{cite journal | vauthors = Lello S | title = Nomegestrol acetate: pharmacology, safety profile and therapeutic efficacy | journal = Drugs | volume = 70 | issue = 5 | pages = 541–559 | date = March 2010 | pmid = 20329803 | doi = 10.2165/11532130-000000000-00000 | s2cid = 24780717 }}</ref>
| protein_bound = 97.5–98.0% (to [[human serum albumin|albumin]])<ref name="Lello2010" />
| protein_bound = 97.5–98.0% (to [[human serum albumin|albumin]])<ref name="Lello2010" />
| metabolism = [[Liver]] (by [[hydroxylation]] via [[CYP3A3]], [[CYP3A4]], [[CYP2A6]])<ref name="Lello2010" />
| metabolism = [[Liver]] (by [[hydroxylation]] via [[CYP3A3]], [[CYP3A4]], [[CYP2A6]])<ref name="Lello2010" />
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}}
}}
<!-- Definition and medical uses -->
<!-- Definition and medical uses -->
'''Nomegestrol acetate''' ('''NOMAC'''), sold under the brand names '''Lutenyl''' and '''Zoely''' among others, is a [[progestin]] medication which is used in [[birth control pills]], [[menopausal hormone therapy]], and for the treatment of [[gynecological disorder]]s.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref><ref name="Lello2010" /><ref name="LemkeWilliams2012">{{cite book|author1=Thomas L. Lemke|author2=David A. Williams|title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1403|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1403–}}</ref><ref name="Shields-BotellaChetrite2005">{{cite journal|last1=Shields-Botella|first1=J.|last2=Chetrite|first2=G.|last3=Meschi|first3=S.|last4=Pasqualini|first4=J.R.|title=Effect of nomegestrol acetate on estrogen biosynthesis and transformation in MCF-7 and T47-D breast cancer cells|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=93|issue=1|year=2005|pages=1–13|issn=0960-0760|doi=10.1016/j.jsbmb.2004.11.004|pmid=15748827}}</ref><ref name="EMA-E2-NOMAC">http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002068/WC500120841.pdf</ref><ref name="TGA-E2-NOMAC">https://www.tga.gov.au/sites/default/files/auspar-zoely.pdf</ref> It is available both alone and in combination with an [[estrogen (medication)|estrogen]].<ref name="Drugs.com">https://www.drugs.com/international/nomegestrol.html</ref><ref name="EMA-Zoely" /> NOMAC is taken [[oral administration|by mouth]].<ref name="pmid16112947" /> A [[contraceptive implant|birth control implant]] for placement [[subcutaneous implant|under the skin]] was also developed but ultimately was not marketed.<ref name="BracheFaundes2002" /><ref name="ErkkolaLandgren2005" /><ref name="Shoupe2011" /><ref name="RoyerJones2014" />
'''Nomegestrol acetate''' ('''NOMAC'''), sold under the brand names '''Lutenyl''' and '''Zoely''' among others, is a [[progestin]] medication which is used in [[birth control pills]], [[menopausal hormone therapy]], and for the treatment of [[gynecological disorder]]s.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref><ref name="Lello2010" /><ref name="LemkeWilliams2012">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1403|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1403–}}</ref><ref name="Shields-BotellaChetrite2005">{{cite journal | vauthors = Shields-Botella J, Chetrite G, Meschi S, Pasqualini JR | title = Effect of nomegestrol acetate on estrogen biosynthesis and transformation in MCF-7 and T47-D breast cancer cells | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 93 | issue = 1 | pages = 1–13 | date = January 2005 | pmid = 15748827 | doi = 10.1016/j.jsbmb.2004.11.004 | s2cid = 25273633 | doi-access = free }}</ref><ref name="EMA-E2-NOMAC">{{cite web | title = Nomegestrol/estradiol assessment report | publisher = European Medicines Agency | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002068/WC500120841.pdf }}</ref><ref name="TGA-E2-NOMAC">{{cite web | title = Australian Public Assessment Report for Nomegestrol acetate/oestradiol | url = https://www.tga.gov.au/sites/default/files/auspar-zoely.pdf | date = October 2011 }}</ref> It is available both alone and in combination with an [[estrogen (medication)|estrogen]].<ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/nomegestrol.html|title = Zoely: Uses, Side Effects, Benefits/Risks}}</ref><ref name="EMA-Zoely" /> NOMAC is taken [[oral administration|by mouth]].<ref name="pmid16112947" /> A [[contraceptive implant|birth control implant]] for placement [[subcutaneous implant|under the skin]] was also developed but ultimately was not marketed.<ref name="BracheFaundes2002" /><ref name="ErkkolaLandgren2005" /><ref name="Shoupe2011" /><ref name="RoyerJones2014" />


<!-- Side effects and mechanism -->
<!-- Side effects and mechanism -->
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<!-- History, society and culture -->
<!-- History, society and culture -->
[[Nomegestrol]], a related compound, was patented in 1975, and NOMAC was described in 1983.<ref name="Elks2014" /><ref name="pmid6683550" /> NOMAC was first introduced for medical use, for the treatment of gynecological disorders and in menopausal hormone therapy, in [[Europe]] in 1986.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> It was subsequently approved in Europe in 2011 as a component of birth control pills.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> NOMAC is available widely throughout the world.<ref name="Drugs.com" /><ref name="IndexNominum2000" /> It is not available in the [[United States]] or [[Canada]].<ref name="Drugs.com" /><ref name="Lello2010" /><ref name="YangPlosker2012">{{cite journal|last1=Yang|first1=Lily P.H.|last2=Plosker|first2=Greg L.|title=Nomegestrol Acetate/Estradiol|journal=Drugs|volume=72|issue=14|year=2012|pages=1917–1928|issn=0012-6667|doi=10.2165/11208180-000000000-00000|pmid=22950535}}</ref><ref name="Burke2013">{{cite journal|last1=Burke|first1=Anne|title=Nomegestrol acetate-17b-estradiol for oral contraception|journal=Patient Preference and Adherence|year=2013|pages=607–19|issn=1177-889X|doi=10.2147/PPA.S39371|pmid=23836965|pmc=3702550|volume=7}}</ref>
[[Nomegestrol]], a related compound, was patented in 1975, and NOMAC was described in 1983.<ref name="Elks2014" /><ref name="pmid6683550" /> NOMAC was first introduced for medical use, for the treatment of gynecological disorders and in menopausal hormone therapy, in [[Europe]] in 1986.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> It was subsequently approved in Europe in 2011 as a component of birth control pills.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> NOMAC is available widely throughout the world.<ref name="Drugs.com" /><ref name="IndexNominum2000" /> It is not available in the [[United States]] or [[Canada]].<ref name="Drugs.com" /><ref name="Lello2010" /><ref name="YangPlosker2012">{{cite journal | vauthors = Yang LP, Plosker GL | title = Nomegestrol acetate/estradiol: in oral contraception | journal = Drugs | volume = 72 | issue = 14 | pages = 1917–1928 | date = October 2012 | pmid = 22950535 | doi = 10.2165/11208180-000000000-00000 | s2cid = 44335732 }}</ref><ref name="Burke2013">{{cite journal | vauthors = Burke A | title = Nomegestrol acetate-17b-estradiol for oral contraception | journal = Patient Preference and Adherence | volume = 7 | pages = 607–619 | year = 2013 | pmid = 23836965 | pmc = 3702550 | doi = 10.2147/PPA.S39371 | doi-access = free }}</ref>


{{TOC limit|3}}
{{TOC limit|3}}


==Medical uses==
==Medical uses==
NOMAC is used alone in the treatment of [[gynecological disorder]]s including [[menstrual disturbance]]s (e.g., [[dysmenorrhea]], [[menorrhagia]], [[oligomenorrhea]], [[polymenorrhea]], [[amenorrhea]]), [[vaginal bleeding]], [[breast pain]], and [[premenstrual syndrome]] and in [[menopausal hormone therapy]].<ref name="Lello2010" /><ref name="Shields-BotellaChetrite2005" /><ref name="Lutenyl-Label">http://www.teva.com.ar/productos/Documents/SmPC/LUTENYL%2003-15.pdf</ref> It is used in combination with [[estradiol (medication)|estradiol]] as a [[birth control pill]] and in menopausal hormone therapy.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> NOMAC-only tablets are also used as a form of [[progestogen-only birth control]], although they are not specifically licensed as such.<ref name="pmid23078975">{{cite journal | vauthors = Gourdy P, Bachelot A, Catteau-Jonard S, Chabbert-Buffet N, Christin-Maître S, Conard J, Fredenrich A, Gompel A, Lamiche-Lorenzini F, Moreau C, Plu-Bureau G, Vambergue A, Vergès B, Kerlan V | title = Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology | journal = Ann. Endocrinol. (Paris) | volume = 73 | issue = 5 | pages = 469–87 | date = November 2012 | pmid = 23078975 | doi = 10.1016/j.ando.2012.09.001 | url = }}</ref>
NOMAC is used alone in the treatment of [[gynecological disorder]]s including [[menstrual disturbance]]s (e.g., [[dysmenorrhea]], [[menorrhagia]], [[oligomenorrhea]], [[polymenorrhea]], [[amenorrhea]]), [[vaginal bleeding]], [[breast pain]], and [[premenstrual syndrome]] and in [[menopausal hormone therapy]].<ref name="Lello2010" /><ref name="Shields-BotellaChetrite2005" /><ref name="Lutenyl-Label">{{Cite web |url=http://www.teva.com.ar/productos/Documents/SmPC/LUTENYL%2003-15.pdf |title= Lutenyl Nomegestrol acetato 5 mg |access-date=2018-01-09 |archive-date=2018-01-09 |archive-url=https://web.archive.org/web/20180109181400/http://www.teva.com.ar/productos/Documents/SmPC/LUTENYL%2003-15.pdf |url-status=dead }}</ref> It is used in combination with [[estradiol (medication)|estradiol]] as a [[birth control pill]] and in menopausal hormone therapy.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> NOMAC-only tablets are also used as a form of [[progestogen-only birth control]], although they are not specifically licensed as such.<ref name="pmid23078975">{{cite journal | vauthors = Gourdy P, Bachelot A, Catteau-Jonard S, Chabbert-Buffet N, Christin-Maître S, Conard J, Fredenrich A, Gompel A, Lamiche-Lorenzini F, Moreau C, Plu-Bureau G, Vambergue A, Vergès B, Kerlan V | display-authors = 6 | title = Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology | journal = Annales d'Endocrinologie | volume = 73 | issue = 5 | pages = 469–487 | date = November 2012 | pmid = 23078975 | doi = 10.1016/j.ando.2012.09.001 }}</ref>


===Available forms===
===Available forms===
NOMAC is available both alone and in combination with estrogens.<ref name="Drugs.com" /><ref name="EMA-Zoely">http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001213/WC500115833.pdf</ref> The following formulations are available:<ref name="Drugs.com" /><ref name="EMA-Zoely" />
NOMAC is available both alone and in combination with estrogens.<ref name="Drugs.com" /><ref name="EMA-Zoely">{{cite web | title = Zoely Assessment Report | publisher = Europeans Medicines Agency | date = 22 March 2011 | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001213/WC500115833.pdf }}</ref> The following formulations are available:<ref name="Drugs.com" /><ref name="EMA-Zoely" />


* NOMAC 3.75&nbsp;mg and 5&nbsp;mg oral tablets (Lutenyl) – indicated for menopausal hormone therapy and gynecological disorders
* NOMAC 3.75&nbsp;mg and 5&nbsp;mg oral tablets (Lutenyl) – indicated for menopausal hormone therapy and gynecological disorders
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==Contraindications==
==Contraindications==
Because NOMAC is [[metabolism|metabolized]] by the [[liver]], [[hepatic impairment]] can result in an accumulation of the medication.<ref name="pmid26327902">{{cite journal | vauthors = Bińkowska M, Woroń J | title = Progestogens in menopausal hormone therapy | journal = PRZ Menopauzalny | volume = 14 | issue = 2 | pages = 134–43 | year = 2015 | pmid = 26327902 | pmc = 4498031 | doi = 10.5114/pm.2015.52154 | url = }}</ref>
Because NOMAC is [[metabolism|metabolized]] by the [[liver]], [[hepatic impairment]] can result in an accumulation of the medication.<ref name="pmid26327902">{{cite journal | vauthors = Bińkowska M, Woroń J | title = Progestogens in menopausal hormone therapy | journal = Przeglad Menopauzalny = Menopause Review | volume = 14 | issue = 2 | pages = 134–143 | date = June 2015 | pmid = 26327902 | pmc = 4498031 | doi = 10.5114/pm.2015.52154 }}</ref>


==Side effects==
==Side effects==
The [[side effect]]s of NOMAC are similar to those of other progestogens.<ref name="Lello2010" /> It is well tolerated and often produces no side effects.<ref name="Lello2010" /> Possible side effects of NOMAC include [[menstrual irregularities]] (e.g., abnormal bleeding or spotting), [[headache]], [[nausea]], [[breast tenderness]], and [[weight gain]].<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="pmid12626173">{{cite journal | vauthors = Rowlands S | title = Newer progestogens | journal = J Fam Plann Reprod Health Care | volume = 29 | issue = 1 | pages = 13–6 | year = 2003 | pmid = 12626173 | doi = 10.1783/147118903101197188| url = | doi-access = free }}</ref><ref name="Lyseng-WilliamsonYang2012">{{cite journal|last1=Lyseng-Williamson|first1=Katherine A.|last2=Yang|first2=Lily P. H.|last3=Plosker|first3=Greg L.|title=Nomegestrol acetate/estradiol: a guide to its use in oral contraception|journal=Drugs & Therapy Perspectives|volume=29|issue=1|year=2012|pages=1–6|issn=1172-0360|doi=10.1007/s40267-012-0005-9}}</ref><ref name="Lutenyl-Label" /> However, body weight is generally unchanged.<ref name="Lello2010" /> Rarely, [[meningioma]]s have been reported in association with NOMAC.<ref name="pmid30783806">{{cite journal | vauthors = Passeri T, Champagne PO, Bernat AL, Hanakita S, Salle H, Mandonnet E, Froelich S | title = Spontaneous regression of meningiomas after interruption of nomegestrol acetate: a series of three patients | journal = Acta Neurochir (Wien) | volume = 161 | issue = 4 | pages = 761–765 | date = April 2019 | pmid = 30783806 | doi = 10.1007/s00701-019-03848-x | url = }}</ref><ref name="pmid30666456">{{cite journal | vauthors = Champagne PO, Passeri T, Froelich S | title = Combined hormonal influence of cyproterone acetate and nomegestrol acetate on meningioma: a case report | journal = Acta Neurochir (Wien) | volume = 161 | issue = 3 | pages = 589–592 | date = March 2019 | pmid = 30666456 | doi = 10.1007/s00701-018-03782-4 | url = }}</ref><ref name="pmid29600913">{{cite journal | vauthors = Amelot A, van Effenterre R, Kalamarides M, Cornu P, Boch AL | title = Natural history of cavernous sinus meningiomas | journal = J. Neurosurg. | volume = 130| issue = 2| pages = 435–442 | date = March 2018 | pmid = 29600913 | doi = 10.3171/2017.7.JNS17662 | url = | doi-access = free }}</ref><ref name="ANSM2019">https://www.ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Luteran-acetate-de-chlormadinone-et-Lutenyl-acetate-de-nomegestrol-et-leurs-generiques-des-cas-de-meningiome-rapportes-Point-d-information</ref>
The [[side effect]]s of NOMAC are similar to those of other progestogens.<ref name="Lello2010" /> It is well tolerated and often produces no side effects.<ref name="Lello2010" /> Possible side effects of NOMAC include [[menstrual irregularities]] (e.g., abnormal bleeding or spotting), [[headache]], [[nausea]], [[breast tenderness]], and [[weight gain]].<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="pmid12626173">{{cite journal | vauthors = Rowlands S | title = Newer progestogens | journal = The Journal of Family Planning and Reproductive Health Care | volume = 29 | issue = 1 | pages = 13–16 | date = January 2003 | pmid = 12626173 | doi = 10.1783/147118903101197188 | doi-access = free }}</ref><ref name="Lyseng-WilliamsonYang2012">{{cite journal| vauthors = Lyseng-Williamson KA, Yang LP, Plosker GL |title=Nomegestrol acetate/estradiol: a guide to its use in oral contraception|journal=Drugs & Therapy Perspectives|volume=29|issue=1|year=2012|pages=1–6|issn=1172-0360|doi=10.1007/s40267-012-0005-9|s2cid=71591520}}</ref><ref name="Lutenyl-Label" /> However, body weight is generally unchanged.<ref name="Lello2010" /> Rarely, [[meningioma]]s have been reported in association with NOMAC.<ref name="pmid30783806">{{cite journal | vauthors = Passeri T, Champagne PO, Bernat AL, Hanakita S, Salle H, Mandonnet E, Froelich S | title = Spontaneous regression of meningiomas after interruption of nomegestrol acetate: a series of three patients | journal = Acta Neurochirurgica | volume = 161 | issue = 4 | pages = 761–765 | date = April 2019 | pmid = 30783806 | doi = 10.1007/s00701-019-03848-x | s2cid = 67750259 }}</ref><ref name="pmid30666456">{{cite journal | vauthors = Champagne PO, Passeri T, Froelich S | title = Combined hormonal influence of cyproterone acetate and nomegestrol acetate on meningioma: a case report | journal = Acta Neurochirurgica | volume = 161 | issue = 3 | pages = 589–592 | date = March 2019 | pmid = 30666456 | doi = 10.1007/s00701-018-03782-4 | s2cid = 58573065 }}</ref><ref name="pmid29600913">{{cite journal | vauthors = Amelot A, van Effenterre R, Kalamarides M, Cornu P, Boch AL | title = Natural history of cavernous sinus meningiomas | journal = Journal of Neurosurgery | volume = 130 | issue = 2 | pages = 435–442 | date = March 2018 | pmid = 29600913 | doi = 10.3171/2017.7.JNS17662 | doi-access = free }}</ref><ref name="ANSM2019">{{Cite web|url=https://www.ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Luteran-acetate-de-chlormadinone-et-Lutenyl-acetate-de-nomegestrol-et-leurs-generiques-des-cas-de-meningiome-rapportes-Point-d-information|title = Actualité - Luteran (Acétate de chlormadinone) et Lutényl (Acétate de nomégestrol) et leurs génériques : Des cas de méningiome rapportés - ANSM}}</ref>


==Overdose==
==Overdose==
There have been no reports of serious [[adverse effect]]s due to [[overdose]] of NOMAC.<ref name="TGA-E2-NOMAC" /> NOMAC has been administered alone at a dosage of up to 40&nbsp;times the recommended dosage, and the combination of NOMAC and estradiol has been administered in multiple doses of up to 5&nbsp;times the recommended dosage to women in clinical trials, and no safety concerns or harmful effects were observed in either case.<ref name="NogestLabel">http://mri.cts-mrp.eu/download/BE_H_0137_001_FinalSPC.pdf</ref><ref name="TGA-E2-NOMAC" /> Symptoms of NOMAC and estradiol overdose might include [[nausea]], [[vomiting]], and, in young girls, slight [[vaginal bleeding]].<ref name="TGA-E2-NOMAC" /> There is no [[antidote]] for NOMAC overdose and treatment of overdose should be based on [[symptom]]s.<ref name="TGA-E2-NOMAC" />
There have been no reports of serious [[adverse effect]]s due to [[overdose]] of NOMAC.<ref name="TGA-E2-NOMAC" /> NOMAC has been administered alone at a dosage of up to 40&nbsp;times the recommended dosage, and the combination of NOMAC and estradiol has been administered in multiple doses of up to 5&nbsp;times the recommended dosage to women in clinical trials, and no safety concerns or harmful effects were observed in either case.<ref name="NogestLabel">{{Cite web |url=http://mri.cts-mrp.eu/download/BE_H_0137_001_FinalSPC.pdf |title= NOGEST, 5 mg tablets |access-date=2018-09-01 |archive-date=2018-09-01 |archive-url=https://web.archive.org/web/20180901215807/http://mri.cts-mrp.eu/download/BE_H_0137_001_FinalSPC.pdf |url-status=dead }}</ref><ref name="TGA-E2-NOMAC" /> Symptoms of NOMAC and estradiol overdose might include [[nausea]], [[vomiting]], and, in young girls, slight [[vaginal bleeding]].<ref name="TGA-E2-NOMAC" /> There is no [[antidote]] for NOMAC overdose and treatment of overdose should be based on [[symptom]]s.<ref name="TGA-E2-NOMAC" />


==Interactions==
== Interactions ==

The [[metabolism]] of NOMAC is dependent on [[CYP3A4]], so [[enzyme inhibitor|inhibitor]]s and [[enzyme inducer|inducer]]s of this enzyme such as [[ketoconazole]] and [[rifampicin]], respectively, as well as some [[anticonvulsant]]s, may pose a clinically significant [[drug interaction]] with NOMAC.<ref name="Lello2010" /><ref name="RuanSeeger2012" /> (For a list of CYP3A4 inhibitors and inducers, see [[CYP3A4#CYP3A4 ligands|here]].)
The [[metabolism]] of NOMAC is dependent on [[CYP3A4]], so [[enzyme inhibitor|inhibitor]]s and [[enzyme inducer|inducer]]s of this enzyme such as [[ketoconazole]] and [[rifampicin]], respectively, as well as some [[anticonvulsant]]s, may pose a clinically significant [[drug interaction]] with NOMAC.<ref name="Lello2010" /><ref name="RuanSeeger2012" /> (For a list of CYP3A4 inhibitors and inducers, see [[CYP3A4#Ligands|here]].)


==Pharmacology==
==Pharmacology==
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| colspan="9" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference [[ligand (biochemistry)|ligand]]s (100%) were [[promegestone]] for the {{abbrlink|PR|progesterone receptor}}, [[metribolone]] for the {{abbrlink|AR|androgen receptor}}, [[estradiol (medication)|estradiol]] for the {{abbrlink|ER|estrogen receptor}}, [[dexamethasone]] for the {{abbrlink|GR|glucocorticoid receptor}}, [[aldosterone]] for the {{abbrlink|MR|mineralocorticoid receptor}}, [[androstanolone|dihydrotestosterone]] for {{abbrlink|SHBG|sex hormone-binding globulin}}, and [[hydrocortisone|cortisol]] for {{abbrlink|CBG|Corticosteroid-binding globulin}}. '''Sources:''' <ref name="pmid16112947" />
| colspan="9" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference [[ligand (biochemistry)|ligand]]s (100%) were [[promegestone]] for the {{abbrlink|PR|progesterone receptor}}, [[metribolone]] for the {{abbrlink|AR|androgen receptor}}, [[estradiol (medication)|estradiol]] for the {{abbrlink|ER|estrogen receptor}}, [[dexamethasone]] for the {{abbrlink|GR|glucocorticoid receptor}}, [[aldosterone]] for the {{abbrlink|MR|mineralocorticoid receptor}}, [[androstanolone|dihydrotestosterone]] for {{abbrlink|SHBG|sex hormone-binding globulin}}, and [[hydrocortisone|cortisol]] for {{abbrlink|CBG|Corticosteroid-binding globulin}}. '''Sources:''' <ref name="pmid16112947" />
|}
|}

====Progestogenic activity====
====Progestogenic activity====
NOMAC is a [[potency (pharmacology)|potent]] and pure [[progestogen (medication)|progestogen]], acting as a selective, high-[[affinity (pharmacology)|affinity]] [[full agonist]] of the [[progesterone receptor]] (PR) (K<sub>i</sub> = 3&nbsp;nM, 67–303% of the [[relative binding affinity]] of [[progesterone (medication)|progesterone]]),<ref name="MueckSitruk-Ware2011">{{cite journal|last1=Mueck|first1=Alfred O.|last2=Sitruk-Ware|first2=Regine|title=Nomegestrol acetate, a novel progestogen for oral contraception|journal=Steroids|volume=76|issue=6|year=2011|pages=531–539|issn=0039-128X|doi=10.1016/j.steroids.2011.02.002|pmid=21335021}}</ref> and is said to have higher potency and substantially improved [[binding selectivity|selectivity]] for the PR relative to [[medroxyprogesterone acetate]] (the 6-[[hydrogen]]ated or non-6-7-[[double bond]]ed [[structural analog|analogue]] of [[megestrol acetate]] and the most widely used progestin).<ref name="LemkeWilliams2012" /><ref name="GoldsteinMeston2005">{{cite book|author1=Irwin Goldstein|author2=Cindy M. Meston|author3=Susan Davis |author4=Abdulmaged Traish |title=Women's Sexual Function and Dysfunction: Study, Diagnosis and Treatment|url=https://books.google.com/books?id=3J7TnwpbZQwC&pg=PA554|date=17 November 2005|publisher=CRC Press|isbn=978-1-84214-263-9|pages=554–}}</ref><ref name="HapgoodAfricander2014">{{cite journal|last1=Hapgood|first1=J.P.|last2=Africander|first2=D.|last3=Louw|first3=R.|last4=Ray|first4=R.M.|last5=Rohwer|first5=J.M.|title=Potency of progestogens used in hormonal therapy: Toward understanding differential actions|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=142|year=2014|pages=39–47|issn=0960-0760|doi=10.1016/j.jsbmb.2013.08.001|pmid=23954501}}</ref> In accordance, NOMAC is a potent [[antigonadotropin]] and exhibits no [[androgen]]ic, [[estrogen (medication)|estrogen]]ic,<ref name="Pasqualini2002">{{cite book|author=Jorge R. Pasqualini|title=Breast Cancer: Prognosis, Treatment, and Prevention|url=https://books.google.com/books?id=l4XLBQAAQBAJ&pg=PA224|date=17 July 2002|publisher=CRC Press|isbn=978-0-203-90924-9|pages=224–}}</ref> [[glucocorticoid]], or [[antimineralocorticoid]] activity,<ref name="Lello2010" /> but does possess some [[antiandrogen]]ic activity.<ref name="MueckSitruk-Ware2011"/><ref name="pmid11791081">{{cite journal | vauthors = Sitruk-Ware R | title = Progestogens in hormonal replacement therapy: new molecules, risks, and benefits | journal = Menopause | volume = 9 | issue = 1 | pages = 6–15 | year = 2002 | pmid = 11791081 | doi = 10.1097/00042192-200201000-00003| url = }}</ref> Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and [[antiestrogen]]ic effects when administered at sufficiently high doses.<ref name="Lello2010" />
NOMAC is a [[potency (pharmacology)|potent]] and pure [[progestogen (medication)|progestogen]], acting as a selective, high-[[affinity (pharmacology)|affinity]] [[full agonist]] of the [[progesterone receptor]] (PR) (K<sub>i</sub> = 3&nbsp;nM, 67–303% of the [[relative binding affinity]] of [[progesterone (medication)|progesterone]]),<ref name="MueckSitruk-Ware2011">{{cite journal | vauthors = Mueck AO, Sitruk-Ware R | title = Nomegestrol acetate, a novel progestogen for oral contraception | journal = Steroids | volume = 76 | issue = 6 | pages = 531–539 | date = May 2011 | pmid = 21335021 | doi = 10.1016/j.steroids.2011.02.002 | s2cid = 27419175 }}</ref> and is said to have higher potency and substantially improved [[binding selectivity|selectivity]] for the PR relative to [[medroxyprogesterone acetate]] (the 6-[[hydrogen]]ated or non-6-7-[[double bond]]ed [[structural analog|analogue]] of [[megestrol acetate]] and the most widely used progestin).<ref name="LemkeWilliams2012" /><ref name="GoldsteinMeston2005">{{cite book| vauthors = Goldstein I, Meston CM, Davis S, Traish A |title=Women's Sexual Function and Dysfunction: Study, Diagnosis and Treatment|url=https://books.google.com/books?id=3J7TnwpbZQwC&pg=PA554|date=17 November 2005|publisher=CRC Press|isbn=978-1-84214-263-9|pages=554–}}</ref><ref name="HapgoodAfricander2014">{{cite journal | vauthors = Hapgood JP, Africander D, Louw R, Ray RM, Rohwer JM | title = Potency of progestogens used in hormonal therapy: toward understanding differential actions | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 142 | pages = 39–47 | date = July 2014 | pmid = 23954501 | doi = 10.1016/j.jsbmb.2013.08.001 | s2cid = 12142015 }}</ref> In accordance, NOMAC is a potent [[antigonadotropin]] and exhibits no [[androgen]]ic, [[estrogen (medication)|estrogen]]ic,<ref name="Pasqualini2002">{{cite book| vauthors = Pasqualini JR |title=Breast Cancer: Prognosis, Treatment, and Prevention|url=https://books.google.com/books?id=l4XLBQAAQBAJ&pg=PA224|date=17 July 2002|publisher=CRC Press|isbn=978-0-203-90924-9|pages=224–}}</ref> [[glucocorticoid]], or [[antimineralocorticoid]] activity,<ref name="Lello2010" /> but does possess some [[antiandrogen]]ic activity.<ref name="MueckSitruk-Ware2011"/><ref name="pmid11791081">{{cite journal | vauthors = Sitruk-Ware R | title = Progestogens in hormonal replacement therapy: new molecules, risks, and benefits | journal = Menopause | volume = 9 | issue = 1 | pages = 6–15 | year = 2002 | pmid = 11791081 | doi = 10.1097/00042192-200201000-00003 | s2cid = 12136231 }}</ref> Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and [[antiestrogen]]ic effects when administered at sufficiently high doses.<ref name="Lello2010" />


Like many other [[progestogen (medication)|progestogen]]s,<ref name="Pasqualini2009a">{{cite journal|last1=Pasqualini|first1=Jorge R.|title=Progestins and breast cancer|journal=Gynecological Endocrinology|volume=23|issue=sup1|year=2009|pages=32–41|issn=0951-3590|doi=10.1080/09513590701585003|pmid=17943537}}</ref><ref name="Pasqualini2009b">{{cite journal|last1=Pasqualini|first1=Jorge R.|title=Breast cancer and steroid metabolizing enzymes: The role of progestogens|journal=Maturitas|volume=65|year=2009|pages=S17–S21|issn=0378-5122|doi=10.1016/j.maturitas.2009.11.006|pmid=19962254}}</ref> NOMAC has been assessed and found ''[[in vitro]]'' to inhibit the conversion of [[estrone sulfate]] to [[estrone]] (via inhibition of [[steroid sulfatase]]) and estrone to estradiol (via inhibition of {{abbrlink|17β-HSD|17β-hydroxysteroid dehydrogenase}}) at high concentrations (0.5–50&nbsp;μM) and to stimulate the conversion of estrone into estrone sulfate (via activation of [[estrogen sulfotransferase]] activity) at low concentrations (0.05–0.5 μM), whilst not affecting [[aromatase]] activity at any tested concentration (up to 10&nbsp;μM).<ref name="Lello2010" /><ref name="Shields-BotellaChetrite2005" /> These activities appear to be PR-dependent, as NOMAC is more potent in producing them in PR-rich cell lines (e.g., [[T47-D]] vs. [[MCF-7]]) and they can be blocked by the PR antagonist [[mifepristone]] (RU-486).<ref name="Shields-BotellaChetrite2005" /> Although the clinical implications of these actions are unclear and they have yet to be confirmed ''[[in vivo]]'' or assessed in [[clinical studies]], it has been suggested that NOMAC and certain other progestins may be useful in the treatment of {{abbrlink|ER|estrogen receptor}}-positive [[breast cancer]] by decreasing levels of [[estrogen]]s in breast tissue.<ref name="Pasqualini2009a" /><ref name="Pasqualini2009b" /> In accordance with this notion, ''in vitro'', NOMAC does not have proliferative effects on breast tissue, does not stimulate breast cell proliferation via {{abbrlink|PGRMC1|progesterone receptor membrane component 1}} (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.<ref name="Del PupBerretta2014">{{cite journal|last1=Del Pup|first1=Lino|last2=Berretta|first2=Massimiliano|last3=Di Francia|first3=Raffaele|last4=Cavaliere|first4=Carla|last5=Di Napoli|first5=Marilena|last6=Facchini|first6=Gaetano|last7=Fiorica|first7=Francesco|last8=Mileto|first8=Mario|last9=Schindler|first9=Adolf E.|title=Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk|journal=Anti-Cancer Drugs|volume=25|issue=7|year=2014|pages=745–750|issn=0959-4973|doi=10.1097/CAD.0000000000000050|pmid=24346139}}</ref>
Like many other [[progestogen (medication)|progestogen]]s,<ref name="Pasqualini2009a">{{cite journal | vauthors = Pasqualini JR | title = Progestins and breast cancer | journal = Gynecological Endocrinology | volume = 23 | issue = sup1 | pages = 32–41 | date = October 2007 | pmid = 17943537 | doi = 10.1080/09513590701585003 | s2cid = 46634314 }}</ref><ref name="Pasqualini2009b">{{cite journal | vauthors = Pasqualini JR | title = Breast cancer and steroid metabolizing enzymes: the role of progestogens | journal = Maturitas | volume = 65 | issue = Suppl 1 | pages = S17–S21 | date = December 2009 | pmid = 19962254 | doi = 10.1016/j.maturitas.2009.11.006 }}</ref> NOMAC has been assessed and found ''[[in vitro]]'' to inhibit the conversion of [[estrone sulfate]] to [[estrone]] (via inhibition of [[steroid sulfatase]]) and estrone to estradiol (via inhibition of {{abbrlink|17β-HSD|17β-hydroxysteroid dehydrogenase}}) at high concentrations (0.5–50&nbsp;μM) and to stimulate the conversion of estrone into estrone sulfate (via activation of [[estrogen sulfotransferase]] activity) at low concentrations (0.05–0.5 μM), whilst not affecting [[aromatase]] activity at any tested concentration (up to 10&nbsp;μM).<ref name="Lello2010" /><ref name="Shields-BotellaChetrite2005" /> These activities appear to be PR-dependent, as NOMAC is more potent in producing them in PR-rich cell lines (e.g., [[T47-D]] vs. [[MCF-7]]) and they can be blocked by the PR antagonist [[mifepristone]] (RU-486).<ref name="Shields-BotellaChetrite2005" /> Although the clinical implications of these actions are unclear and they have yet to be confirmed ''[[in vivo]]'' or assessed in [[clinical studies]], it has been suggested that NOMAC and certain other progestins may be useful in the treatment of {{abbrlink|ER|estrogen receptor}}-positive [[breast cancer]] by decreasing levels of [[estrogen]]s in breast tissue.<ref name="Pasqualini2009a" /><ref name="Pasqualini2009b" /> In accordance with this notion, ''in vitro'', NOMAC does not have proliferative effects on breast tissue, does not stimulate breast cell proliferation via {{abbrlink|PGRMC1|progesterone receptor membrane component 1}} (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.<ref name="Del PupBerretta2014">{{cite journal | vauthors = Del Pup L, Berretta M, Di Francia R, Cavaliere C, Di Napoli M, Facchini G, Fiorica F, Mileto M, Schindler AE | display-authors = 6 | title = Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk | journal = Anti-Cancer Drugs | volume = 25 | issue = 7 | pages = 745–750 | date = August 2014 | pmid = 24346139 | doi = 10.1097/CAD.0000000000000050 | s2cid = 33806950 }}</ref>


====Antigonadotropic effects====
====Antigonadotropic effects====
The [[ovulation]]-inhibiting dosage of NOMAC is 1.5 to 5&nbsp;mg/day.<ref name="Lello2010" /><ref name="pmid16112947" /><ref name="Kuhl2011">{{cite journal | author = Kuhl H | title = Pharmacology of Progestogens | journal = J Reproduktionsmed Endokrinol | year = 2011 | volume = 8 | issue = 1 | pages = 157–177 | url = http://www.kup.at/kup/pdf/10168.pdf}}</ref> Due to its high antigonadotropic activity and its long elimination half-life, the contraceptive effectiveness of NOMAC is maintained even when a dose is missed; clinical studies found no increased incidence of [[pregnancy]] with one missed pill of Zoely or even with two missed pills during days 8 to 17 of the [[menstrual cycle]].<ref name="RuanSeeger2012">{{cite journal|last1=Ruan|first1=Xiangyan|last2=Seeger|first2=Harald|last3=Mueck|first3=Alfred O.|title=The pharmacology of nomegestrol acetate|journal=Maturitas|volume=71|issue=4|year=2012|pages=345–353|issn=0378-5122|doi=10.1016/j.maturitas.2012.01.007|pmid=22364709}}</ref>
The [[ovulation]]-inhibiting dosage of NOMAC is 1.5 to 5&nbsp;mg/day.<ref name="Lello2010" /><ref name="pmid16112947" /><ref name="Kuhl2011">{{cite journal | vauthors = Kuhl H | title = Pharmacology of Progestogens | journal = J Reproduktionsmed Endokrinol | year = 2011 | volume = 8 | issue = 1 | pages = 157–177 | url = http://www.kup.at/kup/pdf/10168.pdf}}</ref> Due to its high antigonadotropic activity and its long elimination half-life, the contraceptive effectiveness of NOMAC is maintained even when a dose is missed; clinical studies found no increased incidence of [[pregnancy]] with one missed pill of Zoely or even with two missed pills during days 8 to 17 of the [[menstrual cycle]].<ref name="RuanSeeger2012">{{cite journal | vauthors = Ruan X, Seeger H, Mueck AO | title = The pharmacology of nomegestrol acetate | journal = Maturitas | volume = 71 | issue = 4 | pages = 345–353 | date = April 2012 | pmid = 22364709 | doi = 10.1016/j.maturitas.2012.01.007 }}</ref>


====Antiandrogenic activity====
====Antiandrogenic activity====
NOMAC acts as an [[receptor antagonist|antagonist]] of the [[androgen receptor]] (AR), with approximately 12 to 31% of the [[relative binding affinity]] of [[testosterone (medication)|testosterone]] for the AR and 42% of the affinity of [[metribolone]] for the AR.<ref name="LemkeWilliams2012" /><ref name="HapgoodAfricander2014" /><ref name="Genazzani2001">{{cite book|author=A.R. Genazzani|title=Hormone Replacement Therapy and Cardiovascular Disease: The Current Status of Research and Practice|url=https://books.google.com/books?id=9vRBX0JqXiAC&pg=PA94|date=15 May 2001|publisher=CRC Press|isbn=978-1-84214-038-3|pages=94–}}</ref><ref name="pmid16112947" /> Estimates of the antiandrogenic potency of NOMAC are mixed, ranging from 5 to 20%, 20 to 30%, and 90% of that of [[cyproterone acetate]] depending on the source.<ref name="MueckSitruk-Ware2011" /><ref name="pmid11791081" /><ref name="pmid16112947" /><ref name="pmid17056444">{{cite journal | vauthors = Wiegratz I, Kuhl H | title = Metabolic and clinical effects of progestogens | journal = Eur J Contracept Reprod Health Care | volume = 11 | issue = 3 | pages = 153–61 | year = 2006 | pmid = 17056444 | doi = 10.1080/13625180600772741 | url = }}</ref><ref name="pmid15669548">{{cite journal | vauthors = Sitruk-Ware R, Husmann F, Thijssen JH, Skouby SO, Fruzzetti F, Hanker J, Huber J, Druckmann R | title = Role of progestins with partial antiandrogenic effects | journal = Climacteric | volume = 7 | issue = 3 | pages = 238–54 | date = September 2004 | pmid = 15669548 | doi = 10.1080/13697130400001307 | url = }}</ref><ref name="pmid8808163">{{cite journal|last1=Kuhl|first1=Herbert|title=Comparative Pharmacology of Newer Progestogens|journal=Drugs|volume=51|issue=2|year=1996|pages=188–215|issn=0012-6667|doi=10.2165/00003495-199651020-00002|pmid=8808163}}</ref> The antiandrogenic activity of NOMAC may be useful in helping to alleviate [[acne]], [[seborrhea]], and other [[androgen-dependent condition|androgen-dependent]] symptoms in women.<ref name="RuanSeeger2012" /><ref name="pmid8808163" />
NOMAC acts as an [[receptor antagonist|antagonist]] of the [[androgen receptor]] (AR), with approximately 12 to 31% of the [[relative binding affinity]] of [[testosterone (medication)|testosterone]] for the AR and 42% of the affinity of [[metribolone]] for the AR.<ref name="LemkeWilliams2012" /><ref name="HapgoodAfricander2014" /><ref name="Genazzani2001">{{cite book| vauthors = Genazzani AR |title=Hormone Replacement Therapy and Cardiovascular Disease: The Current Status of Research and Practice|url=https://books.google.com/books?id=9vRBX0JqXiAC&pg=PA94|date=15 May 2001|publisher=CRC Press|isbn=978-1-84214-038-3|pages=94–}}</ref><ref name="pmid16112947" /> Estimates of the antiandrogenic potency of NOMAC are mixed, ranging from 5 to 20%, 20 to 30%, and 90% of that of [[cyproterone acetate]] depending on the source.<ref name="MueckSitruk-Ware2011" /><ref name="pmid11791081" /><ref name="pmid16112947" /><ref name="pmid17056444">{{cite journal | vauthors = Wiegratz I, Kuhl H | title = Metabolic and clinical effects of progestogens | journal = The European Journal of Contraception & Reproductive Health Care | volume = 11 | issue = 3 | pages = 153–161 | date = September 2006 | pmid = 17056444 | doi = 10.1080/13625180600772741 | s2cid = 27088428 }}</ref><ref name="pmid15669548">{{cite journal | vauthors = Sitruk-Ware R, Husmann F, Thijssen JH, Skouby SO, Fruzzetti F, Hanker J, Huber J, Druckmann R | display-authors = 6 | title = Role of progestins with partial antiandrogenic effects | journal = Climacteric | volume = 7 | issue = 3 | pages = 238–254 | date = September 2004 | pmid = 15669548 | doi = 10.1080/13697130400001307 | s2cid = 23112620 }}</ref><ref name="pmid8808163">{{cite journal | vauthors = Kuhl H | title = Comparative pharmacology of newer progestogens | journal = Drugs | volume = 51 | issue = 2 | pages = 188–215 | date = February 1996 | pmid = 8808163 | doi = 10.2165/00003495-199651020-00002 | s2cid = 1019532 }}</ref> The antiandrogenic activity of NOMAC may be useful in helping to alleviate [[acne]], [[seborrhea]], and other [[androgen-dependent condition|androgen-dependent]] symptoms in women.<ref name="RuanSeeger2012" /><ref name="pmid8808163" />


====Other activity====
====Other activity====
Certain progestins have been found to stimulate the [[cell proliferation|proliferation]] of [[MCF-7]] [[breast cancer]] [[cell (biology)|cell]]s ''[[in vitro]]'', an action that is independent of the classical PRs and is instead mediated via the [[progesterone receptor membrane component-1]] (PGRMC1).<ref name="pmid23758160">{{cite journal | vauthors = Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO | title = Possible role of PGRMC1 in breast cancer development | journal = Climacteric | volume = 16 | issue = 5 | pages = 509–13 | date = October 2013 | pmid = 23758160 | doi = 10.3109/13697137.2013.800038 | url = }}</ref> [[Progesterone (medication)|Progesterone]] and NOMAC, in contrast, act neutrally in this assay.<ref name="pmid23758160" /> It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in [[clinical trial|clinical studies]].<ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and breast cancer | journal = Endocr. Rev. | volume = 41| issue = 2| pages = | date = September 2019 | pmid = 31512725 | doi = 10.1210/endrev/bnz001 | url = }}</ref>
Certain progestins have been found to stimulate the [[cell proliferation|proliferation]] of [[MCF-7]] [[breast cancer]] [[cell (biology)|cell]]s ''[[in vitro]]'', an action that is independent of the classical PRs and is instead mediated via the [[progesterone receptor membrane component-1]] (PGRMC1).<ref name="pmid23758160">{{cite journal | vauthors = Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO | display-authors = 6 | title = Possible role of PGRMC1 in breast cancer development | journal = Climacteric | volume = 16 | issue = 5 | pages = 509–513 | date = October 2013 | pmid = 23758160 | doi = 10.3109/13697137.2013.800038 | s2cid = 29808177 }}</ref> [[Progesterone (medication)|Progesterone]] and NOMAC, in contrast, act neutrally in this assay.<ref name="pmid23758160" /> It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in [[clinical trial|clinical studies]].<ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and Breast Cancer | journal = Endocrine Reviews | volume = 41 | issue = 2 | pages = 320–344 | date = April 2020 | pmid = 31512725 | pmc = 7156851 | doi = 10.1210/endrev/bnz001 | doi-access = free }}</ref>


===Pharmacokinetics===
===Pharmacokinetics===
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==History==
==History==
Nomegestrol was patented in 1975, and NOMAC, under the developmental code name ''TX-066'', was first described in the literature in 1983.<ref name="Elks2014" /><ref name="pmid6683550">{{cite journal | vauthors = Paris J, Thévenot R, Bonnet P, Granero M | title = The pharmacological profile of TX 066 (17 alpha-acetoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione), a new oral progestative | journal = Arzneimittelforschung | volume = 33 | issue = 5 | pages = 710–5 | year = 1983 | pmid = 6683550 | doi = | url = }}</ref> It was developed by Theramex Laboratories, a [[pharmaceutical company]] in [[Monaco]] (a satellite country of [[France]]).<ref name="Lello2010" /> The medication was first introduced in Europe alone or in combination with estradiol under the respective brand names Lutenyl and Naemis<ref name="Shields-BotellaChetrite2005" /> for the treatment of gynecological disorders and menopausal symptoms in 1986, and was subsequently developed and approved in 2011 in Europe as a birth control pill in combination with estradiol under the brand name Zoely.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> As Zoely, NOMAC has been studied in over 4,000 women as a method of birth control.<ref name="RuanSeeger2012" />
Nomegestrol was patented in 1975, and NOMAC, under the developmental code name ''TX-066'', was first described in the literature in 1983.<ref name="Elks2014" /><ref name="pmid6683550">{{cite journal | vauthors = Paris J, Thévenot R, Bonnet P, Granero M | title = The pharmacological profile of TX 066 (17 alpha-acetoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione), a new oral progestative | journal = Arzneimittel-Forschung | volume = 33 | issue = 5 | pages = 710–715 | year = 1983 | pmid = 6683550 }}</ref> It was developed by Theramex Laboratories, a [[pharmaceutical company]] in [[Monaco]] (a satellite country of [[France]]).<ref name="Lello2010" /> The medication was first introduced in Europe alone or in combination with estradiol under the respective brand names Lutenyl and Naemis<ref name="Shields-BotellaChetrite2005" /> for the treatment of gynecological disorders and menopausal symptoms in 1986, and was subsequently developed and approved in 2011 in Europe as a birth control pill in combination with estradiol under the brand name Zoely.<ref name="Lello2010" /><ref name="YangPlosker2012" /><ref name="Burke2013" /> As Zoely, NOMAC has been studied in over 4,000 women as a method of birth control.<ref name="RuanSeeger2012" />


==Society and culture==
==Society and culture==


===Generic names===
===Generic names===
''Nomegestrol acetate'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}.<ref name="Elks2014">{{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PR2|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=883}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA747|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=747–}}</ref><ref name="Drugs.com" /> It is also known by its former developmental code name ''TX-066''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />
''Nomegestrol acetate'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title= The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PR2|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=883}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA747|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=747–}}</ref><ref name="Drugs.com" /> It is also known by its former developmental code name ''TX-066''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />


===Brand names===
===Brand names===
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[[File:Nomegestrol acetate availability.png|thumb|right|400px|Known availability of NOMAC in countries throughout the world (as of August 2018). Alone is NOMAC as a standalone medication. With E2 is in combination with estradiol. Discontinued is no longer available.]]
[[File:Nomegestrol acetate availability.png|thumb|right|400px|Known availability of NOMAC in countries throughout the world (as of August 2018). Alone is NOMAC as a standalone medication. With E2 is in combination with estradiol. Discontinued is no longer available.]]


NOMAC (either alone (e.g., as Lutenyl) or in combination with estradiol (e.g., as Naemis))<ref name="Shields-BotellaChetrite2005" /> is available for the treatment of gynecological disorders and menopausal symptoms in [[Argentina]], [[Belgium]], [[Brazil]], [[Chile]], [[France]],<ref name="LöwyWeisz2005">{{cite journal|last1=Löwy|first1=Ilana|last2=Weisz|first2=George|title=French hormones: progestins and therapeutic variation in France|journal=Social Science & Medicine|volume=60|issue=11|year=2005|pages=2609–2622|issn=0277-9536|doi=10.1016/j.socscimed.2004.10.021|pmid=15814185|author1-link=Ilana Löwy}}</ref><ref name="FoidartBeliard1997">{{cite journal|last1=Foidart|first1=Jean-Michel|last2=Beliard|first2=Aude|last3=Hedon|first3=Bernard|last4=Ochsenbein|first4=Edith|last5=Bernard|first5=Anne-Marie|last6=Bergeron|first6=Christine|last7=Thomas|first7=Jean-Louis|title=Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium|journal=BJOG: An International Journal of Obstetrics and Gynaecology|volume=104|issue=3|year=1997|pages=305–310|issn=1470-0328|doi=10.1111/j.1471-0528.1997.tb11458.x|pmid=9091006}}</ref> [[Georgia (country)|Georgia]], [[Hong Kong]], [[Indonesia]], [[Italy]], [[Lebanon]], [[Lithuania]], [[Malta]], [[Monaco]], the [[Netherlands]], [[Peru]], [[Poland]], [[Portugal]], [[Romania]], [[Slovakia]], [[Taiwan]], [[Tunisia]], [[Turkey]], and [[Vietnam]].<ref name="Drugs.com" /><ref name="Micromedex">http://www.micromedexsolutions.com/micromedex2/{{Dead link|date=April 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="Martindale">{{cite book |editor=Sweetman, Sean C. |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |page=2119 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1}}</ref><ref name="IndexNominum2000" /> As a component of birth control pills with estradiol (under the brand name Zoely), NOMAC is available in [[Argentina]], [[Australia]], [[Austria]], [[Belgium]], [[Chile]], [[Colombia]], [[Croatia]], [[Costa Rica]], [[Denmark]], the [[Dominican Republic]], [[El Salvador]], [[Finland]], [[France]], [[Germany]], [[Guatemala]], [[Honduras]], [[Hungary]], [[Ireland]], [[Israel]], [[Italy]], [[Latvia]], [[Lithuania]], [[Malaysia]], [[Monaco]], the [[Netherlands]], [[New Zealand]], [[Nicaragua]], [[Norway]], [[Panama]], [[Poland]], [[Portugal]], [[Russia]], [[Spain]], [[Slovakia]], [[Sweden]], [[Switzerland]], and the [[United Kingdom]].<ref name="Drugs.com" /><ref name="Micromedex" /><ref name="Martindale" /><ref name="IndexNominum2000" /> It was expected that Zoely would become available in the [[United States]] in 2010,<ref name="LentzLobo2012">{{cite book|author1=Gretchen M Lentz|author2=Rogerio A. Lobo|author3=David M Gershenson |author4=Vern L. Katz |title=Comprehensive Gynecology|url=https://books.google.com/books?id=X5KT_w6Nye8C&pg=PA223|date=21 February 2012|publisher=Elsevier Health Sciences|isbn=978-0-323-09131-2|pages=223–}}</ref> but the {{abbrlink|FDA|Food and Drug Administration}} rejected the {{abbrlink|NDA|New Drug Application}} for Zoely in 2011<ref>http://www.medpagetoday.com/publichealthpolicy/fdageneral/29571</ref> and NOMAC ultimately has not been introduced in any form in this country.<ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | accessdate = 9 December 2016 | url = http://www.accessdata.fda.gov/scripts/cder/daf/}}</ref>
NOMAC (either alone (e.g., as Lutenyl) or in combination with estradiol (e.g., as Naemis))<ref name="Shields-BotellaChetrite2005" /> is available for the treatment of gynecological disorders and menopausal symptoms in [[Argentina]], [[Belgium]], [[Brazil]], [[Chile]], [[France]],<ref name="LöwyWeisz2005">{{cite journal | vauthors = Löwy I, Weisz G | title = French hormones: progestins and therapeutic variation in France | journal = Social Science & Medicine | volume = 60 | issue = 11 | pages = 2609–2622 | date = June 2005 | pmid = 15814185 | doi = 10.1016/j.socscimed.2004.10.021 | author1-link = Ilana Löwy }}</ref><ref name="FoidartBeliard1997">{{cite journal | vauthors = Foidart JM, Béliard A, Hedon B, Ochsenbein E, Bernard AM, Bergeron C, Thomas JL | title = Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium | journal = British Journal of Obstetrics and Gynaecology | volume = 104 | issue = 3 | pages = 305–310 | date = March 1997 | pmid = 9091006 | doi = 10.1111/j.1471-0528.1997.tb11458.x | s2cid = 28718791 }}</ref> [[Georgia (country)|Georgia]], [[Hong Kong]], [[Indonesia]], [[Italy]], [[Lebanon]], [[Lithuania]], [[Malta]], [[Monaco]], the [[Netherlands]], [[Peru]], [[Poland]], [[Portugal]], [[Romania]], [[Slovakia]], [[Taiwan]], [[Tunisia]], [[Turkey]], and [[Vietnam]].<ref name="Drugs.com" /><ref name="Micromedex">http://www.micromedexsolutions.com/micromedex2/{{Dead link|date=April 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="Martindale">{{cite book | veditors = Sweetman SC |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |page=2119 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1}}</ref><ref name="IndexNominum2000" /> As a component of birth control pills with estradiol (under the brand name Zoely), NOMAC is available in [[Argentina]], [[Australia]], [[Austria]], [[Belgium]], [[Chile]], [[Colombia]], [[Croatia]], [[Costa Rica]], [[Denmark]], the [[Dominican Republic]], [[El Salvador]], [[Finland]], [[France]], [[Germany]], [[Guatemala]], [[Honduras]], [[Hungary]], [[Ireland]], [[Israel]], [[Italy]], [[Latvia]], [[Lithuania]], [[Malaysia]], [[Monaco]], the [[Netherlands]], [[New Zealand]], [[Nicaragua]], [[Norway]], [[Panama]], [[Poland]], [[Portugal]], [[Russia]], [[Spain]], [[Slovakia]], [[Sweden]], [[Switzerland]], and the [[United Kingdom]].<ref name="Drugs.com" /><ref name="Micromedex" /><ref name="Martindale" /><ref name="IndexNominum2000" /> It was expected that Zoely would become available in the [[United States]] in 2010,<ref name="LentzLobo2012">{{cite book| vauthors = Lentz GM, Lobo RA, Gershenson DM, Katz VL |title=Comprehensive Gynecology|url=https://books.google.com/books?id=X5KT_w6Nye8C&pg=PA223|date=21 February 2012|publisher=Elsevier Health Sciences|isbn=978-0-323-09131-2|pages=223–}}</ref> but the {{abbrlink|FDA|Food and Drug Administration}} rejected the {{abbrlink|NDA|New Drug Application}} for Zoely in 2011<ref>{{Cite web|url=http://www.medpagetoday.com/publichealthpolicy/fdageneral/29571|title=FDA Turns Down Merck Birth Control Pill, Glaucoma Drug|date=10 November 2011}}</ref> and NOMAC ultimately has not been introduced in any form in this country.<ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 9 December 2016 | url = http://www.accessdata.fda.gov/scripts/cder/daf/}}</ref>


==Research==
==Research==
Under the tentative brand name Uniplant, NOMAC was under development by Theramex as a 38&nbsp;mg or 55&nbsp;mg 4&nbsp;cm [[Silastic]] ([[silicone]]-[[plastic]]) [[subcutaneous implant|subcutaneous]] [[birth control implant]] of one-year duration (75&nbsp;ug/day or 100&nbsp;μg/day release rate) in [[Brazil]] from the 1990s and was extensively studied for this purpose in [[clinical trial]]s.<ref name="BracheFaundes2002">{{cite journal|last1=Brache|first1=V.|last2=Faundes|first2=A.|last3=Alvarez|first3=F.|last4=Cochon|first4=L.|title=Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials|journal=Contraception|volume=65|issue=1|year=2002|pages=63–74|issn=0010-7824|doi=10.1016/S0010-7824(01)00289-X|pmid=11861056}}</ref><ref name="ErkkolaLandgren2005">{{cite journal|last1=Erkkola|first1=Risto|last2=Landgren|first2=Britt-Marie|title=Role of progestins in contraception|journal=Acta Obstetricia et Gynecologica Scandinavica|volume=84|issue=3|year=2005|pages=207–216|issn=0001-6349|doi=10.1111/j.0001-6349.2005.00759.x|pmid=15715527}}</ref><ref name="Shoupe2011">{{cite book|author=Donna Shoupe|title=Contraception|url=https://books.google.com/books?id=ksjJcx1CeKcC&pg=PA62|date=10 February 2011|publisher=John Wiley & Sons|isbn=978-1-4443-4263-5|pages=62–}}</ref><ref name="RoyerJones2014">{{cite journal|last1=Royer|first1=Pamela A.|last2=Jones|first2=Kirtly P.|title=Progestins for Contraception|journal=Clinical Obstetrics and Gynecology|volume=57|issue=4|year=2014|pages=644–658|issn=0009-9201|doi=10.1097/GRF.0000000000000072|pmid=25314087}}</ref> The clinical studies included 19,900 women-months of use and demonstrated a one-year failure rate of 0.94%. Uniplant was regarded as showing high effectiveness, and was well tolerated.<ref name="RoyerJones2014" /> In spite of this however, "[f]urther plans to make it available have been deferred by decision of the company holding the progestin patent",<ref name="Croxatto2000">{{cite journal|last1=Croxatto|first1=H|title=Progestin implants|journal=Steroids|volume=65|issue=10–11|year=2000|pages=681–685|issn=0039-128X|doi=10.1016/S0039-128X(00)00124-0|pmid=11108876}}</ref> and, although it continued to be investigated as late as 2006,<ref name="BarbosaMaia2006">{{cite journal|last1=Barbosa|first1=Ione Cristina|last2=Maia|first2=Hugo|last3=Coutinho|first3=Elsimar|last4=Lopes|first4=Renata|last5=Lopes|first5=Antonio C.V.|last6=Noronha|first6=Cristina|last7=Botto|first7=Adelmo|title=Effects of a single Silastic® contraceptive implant containing nomegestrol acetate (Uniplant) on endometrial morphology and ovarian function for 1 year|journal=Contraception|volume=74|issue=6|year=2006|pages=492–497|issn=0010-7824|doi=10.1016/j.contraception.2006.07.013|pmid=17157108|url=http://repositorio.ufba.br/ri/bitstream/ri/6314/1/BB.pdf}}</ref> the implant ultimately never became commercially available.<ref name="Croxatt2002">{{cite journal|last1=Croxatt|first1=Horacio B.|title=Progestin implants for female contraception|journal=Contraception|volume=65|issue=1|year=2002|pages=15–19|issn=0010-7824|doi=10.1016/S0010-7824(01)00293-1|pmid=11861051}}</ref><ref name="McDonald-MosleyBurke2010">{{cite journal|last1=McDonald-Mosley|first1=Raegan|last2=Burke|first2=Anne|title=Contraceptive Implants|journal=Seminars in Reproductive Medicine|volume=28|issue=2|year=2010|pages=110–117|issn=1526-8004|doi=10.1055/s-0030-1248135|pmid=20352560}}</ref>
Under the tentative brand name Uniplant, NOMAC was under development by Theramex as a 38&nbsp;mg or 55&nbsp;mg 4&nbsp;cm [[Silastic]] ([[silicone]]-[[plastic]]) [[subcutaneous implant|subcutaneous]] [[birth control implant]] of one-year duration (75&nbsp;ug/day or 100&nbsp;μg/day release rate) in [[Brazil]] from the 1990s and was extensively studied for this purpose in [[clinical trial]]s.<ref name="BracheFaundes2002">{{cite journal | vauthors = Brache V, Faundes A, Alvarez F, Cochon L | title = Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials | journal = Contraception | volume = 65 | issue = 1 | pages = 63–74 | date = January 2002 | pmid = 11861056 | doi = 10.1016/S0010-7824(01)00289-X }}</ref><ref name="ErkkolaLandgren2005">{{cite journal | vauthors = Erkkola R, Landgren BM | title = Role of progestins in contraception | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 84 | issue = 3 | pages = 207–216 | date = March 2005 | pmid = 15715527 | doi = 10.1111/j.0001-6349.2005.00759.x | s2cid = 6887415 | doi-access = free }}</ref><ref name="Shoupe2011">{{cite book| vauthors = Shoupe D |title=Contraception|url=https://books.google.com/books?id=ksjJcx1CeKcC&pg=PA62|date=10 February 2011|publisher=John Wiley & Sons|isbn=978-1-4443-4263-5|pages=62–}}</ref><ref name="RoyerJones2014">{{cite journal | vauthors = Royer PA, Jones KP | title = Progestins for contraception: modern delivery systems and novel formulations | journal = Clinical Obstetrics and Gynecology | volume = 57 | issue = 4 | pages = 644–658 | date = December 2014 | pmid = 25314087 | doi = 10.1097/GRF.0000000000000072 }}</ref> The clinical studies included 19,900 women-months of use and demonstrated a one-year failure rate of 0.94%. Uniplant was regarded as showing high effectiveness, and was well tolerated.<ref name="RoyerJones2014" /> In spite of this however, "[f]urther plans to make it available have been deferred by decision of the company holding the progestin patent",<ref name="Croxatto2000">{{cite journal | vauthors = Croxatto HB | title = Progestin implants | journal = Steroids | volume = 65 | issue = 10–11 | pages = 681–685 | year = 2000 | pmid = 11108876 | doi = 10.1016/S0039-128X(00)00124-0 | s2cid = 42296395 }}</ref> and, although it continued to be investigated as late as 2006,<ref name="BarbosaMaia2006">{{cite journal | vauthors = Barbosa IC, Maia H, Coutinho E, Lopes R, Lopes AC, Noronha C, Botto A | title = Effects of a single Silastic contraceptive implant containing nomegestrol acetate (Uniplant) on endometrial morphology and ovarian function for 1 year | journal = Contraception | volume = 74 | issue = 6 | pages = 492–497 | date = December 2006 | pmid = 17157108 | doi = 10.1016/j.contraception.2006.07.013 | url = http://www.repositorio.ufba.br/ri/handle/ri/6314 }}</ref> the implant ultimately never became commercially available.<ref name="Croxatt2002">{{cite journal | vauthors = Croxatt HB | title = Progestin implants for female contraception | journal = Contraception | volume = 65 | issue = 1 | pages = 15–19 | date = January 2002 | pmid = 11861051 | doi = 10.1016/S0010-7824(01)00293-1 }}</ref><ref name="McDonald-MosleyBurke2010">{{cite journal | vauthors = McDonald-Mosley R, Burke AE | title = Contraceptive implants | journal = Seminars in Reproductive Medicine | volume = 28 | issue = 2 | pages = 110–117 | date = March 2010 | pmid = 20352560 | doi = 10.1055/s-0030-1248135 | s2cid = 38781450 }}</ref>


Oral NOMAC was under development for the treatment of [[breast cancer]] and for use as a [[progestogen-only pill]] for birth control but did not complete development for these indications.<ref name="AdisInsight-NOMAC">https://adisinsight.springer.com/drugs/800010246</ref> An estradiol and NOMAC [[vaginal ring]] was under development for use in birth control and to treat [[dysmenorrhea]] but did not complete development and was not marketed.<ref name="AdisInsight-E2-NOMAC-ring">https://adisinsight.springer.com/drugs/800036861</ref> A continuous oral formulation of estradiol and NOMAC was under development for the treatment of menopausal symptoms and the treatment or prevention of [[postmenopausal osteoporosis]] but did not complete development.<ref name="AdisInsight-E2-NOMAC-Conti">https://adisinsight.springer.com/drugs/800010259</ref>
Oral NOMAC was under development for the treatment of [[breast cancer]] and for use as a [[progestogen-only pill]] for birth control but did not complete development for these indications.<ref name="AdisInsight-NOMAC">{{Cite web|url=https://adisinsight.springer.com/drugs/800010246|title=Nomegestrol oral | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> An estradiol and NOMAC [[vaginal ring]] was under development for use in birth control and to treat [[dysmenorrhea]] but did not complete development and was not marketed.<ref name="AdisInsight-E2-NOMAC-ring">{{Cite web|url=https://adisinsight.springer.com/drugs/800036861|title=Estradiol/Nomegestrol intravaginal ring | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> A continuous oral formulation of estradiol and NOMAC was under development for the treatment of menopausal symptoms and the treatment or prevention of [[postmenopausal osteoporosis]] but did not complete development.<ref name="AdisInsight-E2-NOMAC-Conti">{{Cite web |url=https://adisinsight.springer.com/drugs/800010259 |title=Estradiol/Nomegestrol continuous | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref>


==References==
== References ==
{{Reflist}}
{{Reflist}}


==Further reading==
== Further reading ==
{{refbegin}}
* {{cite journal|last1=Lello|first1=Stefano|title=Nomegestrol Acetate: Pharmacology, Safety Profile and Therapeutic efficacy|journal=Drugs|volume=70|issue=5|year=2010|pages=541–559|issn=0012-6667|doi=10.2165/11532130-000000000-00000|pmid=20329803}}
* {{cite journal|last1=Mueck|first1=Alfred O.|last2=Sitruk-Ware|first2=Regine|title=Nomegestrol Acetate, a Novel Progestogen for Oral Contraception|journal=Steroids|volume=76|issue=6|year=2011|pages=531–539|issn=0039-128X|doi=10.1016/j.steroids.2011.02.002|pmid=21335021}}
* {{cite journal | vauthors = Lello S | title = Nomegestrol acetate: pharmacology, safety profile and therapeutic efficacy | journal = Drugs | volume = 70 | issue = 5 | pages = 541–559 | date = March 2010 | pmid = 20329803 | doi = 10.2165/11532130-000000000-00000 | s2cid = 24780717 }}
* {{cite journal|last1=Ruan|first1=Xiangyan|last2=Seeger|first2=Harald|last3=Mueck|first3=Alfred O.|title=The pharmacology of nomegestrol acetate|journal=Maturitas|volume=71|issue=4|year=2012|pages=345–353|issn=0378-5122|doi=10.1016/j.maturitas.2012.01.007|pmid=22364709}}
* {{cite journal | vauthors = Mueck AO, Sitruk-Ware R | title = Nomegestrol acetate, a novel progestogen for oral contraception | journal = Steroids | volume = 76 | issue = 6 | pages = 531–539 | date = May 2011 | pmid = 21335021 | doi = 10.1016/j.steroids.2011.02.002 | s2cid = 27419175 }}
* {{cite journal|last1=van Diepen|first1=Harry A|title=Preclinical pharmacological profile of nomegestrol acetate, a synthetic 19-nor-progesterone derivative|journal=Reproductive Biology and Endocrinology|volume=10|issue=1|year=2012|pages=85|issn=1477-7827|doi=10.1186/1477-7827-10-85|pmid=23043680|pmc=3571880}}
* {{cite journal | vauthors = Ruan X, Seeger H, Mueck AO | title = The pharmacology of nomegestrol acetate | journal = Maturitas | volume = 71 | issue = 4 | pages = 345–353 | date = April 2012 | pmid = 22364709 | doi = 10.1016/j.maturitas.2012.01.007 }}
* {{cite journal | vauthors = van Diepen HA | title = Preclinical pharmacological profile of nomegestrol acetate, a synthetic 19-nor-progesterone derivative | journal = Reproductive Biology and Endocrinology | volume = 10 | issue = 1 | pages = 85 | date = October 2012 | pmid = 23043680 | pmc = 3571880 | doi = 10.1186/1477-7827-10-85 | doi-access = free }}
* {{cite journal|last1=Yang|first1=Lily P.H.|last2=Plosker|first2=Greg L.|title=Nomegestrol Acetate/Estradiol|journal=Drugs|volume=72|issue=14|year=2012|pages=1917–1928|issn=0012-6667|doi=10.2165/11208180-000000000-00000|pmid=22950535}}
* {{cite journal|last1=Burke|first1=Anne|title=Nomegestrol acetate-17b-estradiol for oral contraception|journal=Patient Preference and Adherence|year=2013|pages=607–19|issn=1177-889X|doi=10.2147/PPA.S39371|pmid=23836965|pmc=3702550|volume=7}}
* {{cite journal | vauthors = Yang LP, Plosker GL | title = Nomegestrol acetate/estradiol: in oral contraception | journal = Drugs | volume = 72 | issue = 14 | pages = 1917–1928 | date = October 2012 | pmid = 22950535 | doi = 10.2165/11208180-000000000-00000 | s2cid = 44335732 }}
* {{cite journal | vauthors = Burke A | title = Nomegestrol acetate-17b-estradiol for oral contraception | journal = Patient Preference and Adherence | volume = 7 | pages = 607–619 | year = 2013 | pmid = 23836965 | pmc = 3702550 | doi = 10.2147/PPA.S39371 | doi-access = free }}
{{refend}}


{{Progestogens and antiprogestogens}}
{{Progestogens and antiprogestogens}}
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[[Category:Antigonadotropins]]
[[Category:Diketones]]
[[Category:Diketones]]
[[Category:Merck & Co. brands]]
[[Category:Drugs developed by Merck & Co.]]
[[Category:Hormonal contraception]]
[[Category:Hormonal contraception]]
[[Category:Implants (medicine)]]
[[Category:Implants (medicine)]]

Revision as of 19:51, 20 December 2023

Nomegestrol acetate
Clinical data
Trade namesAlone: Lutenyl
With E2: Naemis, Zoely
Other namesNOMAC; NOMAc; Nomegesterol acetate; TX-066; TX-525; ORG-10486-0; Uniplant; 19-Normegestrol acetate; 6-Methyl-17α-acetoxy-δ6-19-norprogesterone; 17α-Acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione
License data
Routes of
administration
By mouth[1]
Drug classProgestogen; Progestin; Progestogen ester; Steroidal antiandrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability63%[1]
Protein binding97.5–98.0% (to albumin)[1]
MetabolismLiver (by hydroxylation via CYP3A3, CYP3A4, CYP2A6)[1]
MetabolitesSix main metabolites, all essentially inactive[1]
Elimination half-life~50 hours (range 30–80 hours)[1][2]
ExcretionUrine, feces[1]
Identifiers
  • [(8S,9S,10R,13S,14S,17R)-17-acetyl-6,13-dimethyl-3-oxo-1,2,8,9,10,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.055.781 Edit this at Wikidata
Chemical and physical data
FormulaC23H30O4
Molar mass370.489 g·mol−1
3D model (JSmol)
  • CC1=CC2C(CCC3(C2CCC3(C(=O)C)OC(=O)C)C)C4C1=CC(=O)CC4
  • InChI=1S/C23H30O4/c1-13-11-20-18(17-6-5-16(26)12-19(13)17)7-9-22(4)21(20)8-10-23(22,14(2)24)27-15(3)25/h11-12,17-18,20-21H,5-10H2,1-4H3/t17-,18-,20-,21+,22+,23+/m1/s1
  • Key:IIVBFTNIGYRNQY-YQLZSBIMSA-N

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders.[3][1][4][5][6][7] It is available both alone and in combination with an estrogen.[8][9] NOMAC is taken by mouth.[3] A birth control implant for placement under the skin was also developed but ultimately was not marketed.[10][11][12][13]

Side effects of NOMAC include menstrual irregularities, headaches, nausea, breast tenderness, and others.[1][14] NOMAC is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[3] It has some antiandrogenic activity and no other important hormonal activity.[3]

Nomegestrol, a related compound, was patented in 1975, and NOMAC was described in 1983.[15][16] NOMAC was first introduced for medical use, for the treatment of gynecological disorders and in menopausal hormone therapy, in Europe in 1986.[1][17][18] It was subsequently approved in Europe in 2011 as a component of birth control pills.[1][17][18] NOMAC is available widely throughout the world.[8][19] It is not available in the United States or Canada.[8][1][17][18]

Medical uses

NOMAC is used alone in the treatment of gynecological disorders including menstrual disturbances (e.g., dysmenorrhea, menorrhagia, oligomenorrhea, polymenorrhea, amenorrhea), vaginal bleeding, breast pain, and premenstrual syndrome and in menopausal hormone therapy.[1][5][14] It is used in combination with estradiol as a birth control pill and in menopausal hormone therapy.[1][17][18] NOMAC-only tablets are also used as a form of progestogen-only birth control, although they are not specifically licensed as such.[20]

Available forms

NOMAC is available both alone and in combination with estrogens.[8][9] The following formulations are available:[8][9]

  • NOMAC 3.75 mg and 5 mg oral tablets (Lutenyl) – indicated for menopausal hormone therapy and gynecological disorders
  • NOMAC 3.75 mg and estradiol 1.5 mg oral tablets (Naemis) – indicated for menopausal hormone therapy
  • NOMAC 2.5 mg and estradiol 1.5 mg oral tablets (Zoely) – indicated for birth control

The availability of these formulations differs by country.[8]

Contraindications

Because NOMAC is metabolized by the liver, hepatic impairment can result in an accumulation of the medication.[21]

Side effects

The side effects of NOMAC are similar to those of other progestogens.[1] It is well tolerated and often produces no side effects.[1] Possible side effects of NOMAC include menstrual irregularities (e.g., abnormal bleeding or spotting), headache, nausea, breast tenderness, and weight gain.[1][17][22][23][14] However, body weight is generally unchanged.[1] Rarely, meningiomas have been reported in association with NOMAC.[24][25][26][27]

Overdose

There have been no reports of serious adverse effects due to overdose of NOMAC.[7] NOMAC has been administered alone at a dosage of up to 40 times the recommended dosage, and the combination of NOMAC and estradiol has been administered in multiple doses of up to 5 times the recommended dosage to women in clinical trials, and no safety concerns or harmful effects were observed in either case.[28][7] Symptoms of NOMAC and estradiol overdose might include nausea, vomiting, and, in young girls, slight vaginal bleeding.[7] There is no antidote for NOMAC overdose and treatment of overdose should be based on symptoms.[7]

Interactions

The metabolism of NOMAC is dependent on CYP3A4, so inhibitors and inducers of this enzyme such as ketoconazole and rifampicin, respectively, as well as some anticonvulsants, may pose a clinically significant drug interaction with NOMAC.[1][2] (For a list of CYP3A4 inhibitors and inducers, see here.)

Pharmacology

Pharmacodynamics

NOMAC has progestogenic activity, antigonadotropic effects, antiandrogenic activity, and no other important hormonal activity.[3]

Relative affinities (%) of nomegestrol acetate and related steroids
Compound PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin CBGTooltip Corticosteroid binding globulin
Nomegestrol acetate 125 42 0 6 0 0 0
Megestrol acetate 65 5 0 30 0 0 0
Progesterone 50 0 0 10 100 0 36
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Sources: [3]

Progestogenic activity

NOMAC is a potent and pure progestogen, acting as a selective, high-affinity full agonist of the progesterone receptor (PR) (Ki = 3 nM, 67–303% of the relative binding affinity of progesterone),[29] and is said to have higher potency and substantially improved selectivity for the PR relative to medroxyprogesterone acetate (the 6-hydrogenated or non-6-7-double bonded analogue of megestrol acetate and the most widely used progestin).[4][30][31] In accordance, NOMAC is a potent antigonadotropin and exhibits no androgenic, estrogenic,[32] glucocorticoid, or antimineralocorticoid activity,[1] but does possess some antiandrogenic activity.[29][33] Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and antiestrogenic effects when administered at sufficiently high doses.[1]

Like many other progestogens,[34][35] NOMAC has been assessed and found in vitro to inhibit the conversion of estrone sulfate to estrone (via inhibition of steroid sulfatase) and estrone to estradiol (via inhibition of 17β-HSDTooltip 17β-hydroxysteroid dehydrogenase) at high concentrations (0.5–50 μM) and to stimulate the conversion of estrone into estrone sulfate (via activation of estrogen sulfotransferase activity) at low concentrations (0.05–0.5 μM), whilst not affecting aromatase activity at any tested concentration (up to 10 μM).[1][5] These activities appear to be PR-dependent, as NOMAC is more potent in producing them in PR-rich cell lines (e.g., T47-D vs. MCF-7) and they can be blocked by the PR antagonist mifepristone (RU-486).[5] Although the clinical implications of these actions are unclear and they have yet to be confirmed in vivo or assessed in clinical studies, it has been suggested that NOMAC and certain other progestins may be useful in the treatment of ERTooltip estrogen receptor-positive breast cancer by decreasing levels of estrogens in breast tissue.[34][35] In accordance with this notion, in vitro, NOMAC does not have proliferative effects on breast tissue, does not stimulate breast cell proliferation via PGRMC1Tooltip progesterone receptor membrane component 1 (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.[36]

Antigonadotropic effects

The ovulation-inhibiting dosage of NOMAC is 1.5 to 5 mg/day.[1][3][37] Due to its high antigonadotropic activity and its long elimination half-life, the contraceptive effectiveness of NOMAC is maintained even when a dose is missed; clinical studies found no increased incidence of pregnancy with one missed pill of Zoely or even with two missed pills during days 8 to 17 of the menstrual cycle.[2]

Antiandrogenic activity

NOMAC acts as an antagonist of the androgen receptor (AR), with approximately 12 to 31% of the relative binding affinity of testosterone for the AR and 42% of the affinity of metribolone for the AR.[4][31][38][3] Estimates of the antiandrogenic potency of NOMAC are mixed, ranging from 5 to 20%, 20 to 30%, and 90% of that of cyproterone acetate depending on the source.[29][33][3][39][40][41] The antiandrogenic activity of NOMAC may be useful in helping to alleviate acne, seborrhea, and other androgen-dependent symptoms in women.[2][41]

Other activity

Certain progestins have been found to stimulate the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[42] Progesterone and NOMAC, in contrast, act neutrally in this assay.[42] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[43]

Pharmacokinetics

NOMAC is well-absorbed, with an oral bioavailability of 63%.[1] It is 97.5 to 98% protein-bound, to albumin, and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin.[1] The medication is metabolized hepatically via hydroxylation by the enzymes CYP3A3, CYP3A4, and CYP2A6.[1] It has six main metabolites, all of which have no or minimal progestogenic activity.[1] The elimination half-life of NOMAC is approximately 50 hours, with a range of 30 to 80 hours.[1][2] Steady-state concentrations of NOMAC are achieved after five days of repeated administration.[1] As Zoely (2.5 mg/day NOMAC), the average circulating concentrations of NOMAC are 4.5 ng/mL at steady-state, with minimum and maximum concentrations of 3.1 ng/mL and 12.3 ng/mL, respectively.[2] The medication is eliminated via urine and feces.[1]

Chemistry

NOMAC, also known as 17α-acetoxy-6-methyl-δ6-19-norprogesterone or as 17α-acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone belonging to the 19-norprogesterone and 17α-hydroxyprogesterone groups.[15] NOMAC is the C17α acetate ester of nomegestrol and the 19-demethylated (or 19-nor) analogue of megestrol acetate, and can also be referred to as 19-normegestrol acetate.[15][4]

History

Nomegestrol was patented in 1975, and NOMAC, under the developmental code name TX-066, was first described in the literature in 1983.[15][16] It was developed by Theramex Laboratories, a pharmaceutical company in Monaco (a satellite country of France).[1] The medication was first introduced in Europe alone or in combination with estradiol under the respective brand names Lutenyl and Naemis[5] for the treatment of gynecological disorders and menopausal symptoms in 1986, and was subsequently developed and approved in 2011 in Europe as a birth control pill in combination with estradiol under the brand name Zoely.[1][17][18] As Zoely, NOMAC has been studied in over 4,000 women as a method of birth control.[2]

Society and culture

Generic names

Nomegestrol acetate is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name.[15][19][8] It is also known by its former developmental code name TX-066.[15][19][8]

Brand names

NOMAC is marketed in combination with estradiol as a birth control pill primarily under the brand name Zoely, in combination with estradiol for use in menopausal hormone therapy primarily under the brand name Naemis, and as a standalone medication for use in menopausal hormone therapy and the treatment of gynecological disorders primarily under the brand name Lutenyl.[8] NOMAC is also marketed alone or in combination with estradiol under a variety of other less common brand names throughout the world.[8]

Availability

Known availability of NOMAC in countries throughout the world (as of August 2018). Alone is NOMAC as a standalone medication. With E2 is in combination with estradiol. Discontinued is no longer available.

NOMAC (either alone (e.g., as Lutenyl) or in combination with estradiol (e.g., as Naemis))[5] is available for the treatment of gynecological disorders and menopausal symptoms in Argentina, Belgium, Brazil, Chile, France,[44][45] Georgia, Hong Kong, Indonesia, Italy, Lebanon, Lithuania, Malta, Monaco, the Netherlands, Peru, Poland, Portugal, Romania, Slovakia, Taiwan, Tunisia, Turkey, and Vietnam.[8][46][47][19] As a component of birth control pills with estradiol (under the brand name Zoely), NOMAC is available in Argentina, Australia, Austria, Belgium, Chile, Colombia, Croatia, Costa Rica, Denmark, the Dominican Republic, El Salvador, Finland, France, Germany, Guatemala, Honduras, Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Malaysia, Monaco, the Netherlands, New Zealand, Nicaragua, Norway, Panama, Poland, Portugal, Russia, Spain, Slovakia, Sweden, Switzerland, and the United Kingdom.[8][46][47][19] It was expected that Zoely would become available in the United States in 2010,[48] but the FDATooltip Food and Drug Administration rejected the NDATooltip New Drug Application for Zoely in 2011[49] and NOMAC ultimately has not been introduced in any form in this country.[50]

Research

Under the tentative brand name Uniplant, NOMAC was under development by Theramex as a 38 mg or 55 mg 4 cm Silastic (silicone-plastic) subcutaneous birth control implant of one-year duration (75 ug/day or 100 μg/day release rate) in Brazil from the 1990s and was extensively studied for this purpose in clinical trials.[10][11][12][13] The clinical studies included 19,900 women-months of use and demonstrated a one-year failure rate of 0.94%. Uniplant was regarded as showing high effectiveness, and was well tolerated.[13] In spite of this however, "[f]urther plans to make it available have been deferred by decision of the company holding the progestin patent",[51] and, although it continued to be investigated as late as 2006,[52] the implant ultimately never became commercially available.[53][54]

Oral NOMAC was under development for the treatment of breast cancer and for use as a progestogen-only pill for birth control but did not complete development for these indications.[55] An estradiol and NOMAC vaginal ring was under development for use in birth control and to treat dysmenorrhea but did not complete development and was not marketed.[56] A continuous oral formulation of estradiol and NOMAC was under development for the treatment of menopausal symptoms and the treatment or prevention of postmenopausal osteoporosis but did not complete development.[57]

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Further reading