Nomegestrol acetate

Nomegestrol acetate
Clinical data
Trade names Alone: Lutenyl
With E2: Naemis, Zoely
Routes of
Oral, subdermal implant[1]
ATC code G03DB04 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 63%[1]
Protein binding 97.5–98% (to albumin)[1]
Metabolism Hepatic (via hydroxylation by CYP3A3, CYP3A4, CYP2A6)[1]
Metabolites Six main metabolites, all essentially inactive[1]
Biological half-life ~50 hours (range 30–80 hours)[1][2]
Excretion Urine, feces[1]
Synonyms NOMAC; NOMAc; TX-066; Uniplant; 19-Normegestrol acetate; 6-Methyl-17α-acetoxy-6-19-norprogesterone
CAS Number 58652-20-3
PubChem (CID) 91668
ChemSpider 82771
UNII 83J78V5W05
KEGG D08281
Chemical and physical data
Formula C23H30O4
Molar mass 370.4819 g/mol
3D model (Jmol) Interactive image

Nomegestrol acetate (NOMAC) (INN, USAN, USAN) (brand names Lutenyl (alone) and Naemis,[3] Zoely (with estradiol)), or 19-normegestrol acetate, also known as 17α-acetoxy-6-dehydro-6-methyl-19-norprogesterone or 17α-acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione, is an steroidal progestin of the 19-norprogesterone and 17α-hydroxyprogesterone groups which was first introduced in the 1980s and is used orally in the treatment of gynecological disorders and menopausal symptoms and as a hormonal contraceptive.[1][4][5][6] It is widely available in Europe and in many other countries throughout the world,[5] though notably not in the United States.[1][7][8][9] NOMAC is the 17α-acetylated derivative of nomegestrol[4] and the 19-demethylated (or 19-nor) analogue of megestrol acetate.[6]

Medical uses

NOMAC is used alone (as Lutenyl) or in combination with estradiol (as Naemis) for the treatment of menstrual disturbances (e.g., dysmenorrhea, menorrhagia) and premenstrual syndrome and as a component of hormone replacement therapy for menopause.[1][3] It is also used as an oral contraceptive with estradiol (as Zoely).[1][7][8]


Hepatic impairment

Because NOMAC is metabolized by the liver, hepatic impairment can result in an accumulation of the drug.[10]

Side effects

Side effects of NOMAC are infrequent and may include acne, abnormal withdrawal bleeding (usually shorter, lighter, or absent menstruations), headache, and weight gain.[7][11][12]


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.)


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 RBA of progesterone),[13] 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).[6][14][15] In accordance, NOMAC is a potent antigonadotropin and exhibits no androgenic, estrogenic,[16] glucocorticoid, or antimineralocorticoid activity,[1] but does possess some antiandrogenic activity (see below).[13][17] Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and antiestrogenic effects when administered at sufficiently high dosages.[1]

Due to the high antigonadotropic activity of NOMAC and its long elimination half-life, its contraceptive effectiveness 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]

Inhibition of estrogen biosynthesis in breast tissue

Like many other progestogens,[18][19] 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-HSD) 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][3] 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).[3] 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 ER-positive breast cancer by decreasing levels of estrogen in breast tissue.[18][19] In accordance with this notion, in vitro, NOMAC does not have proliferative effects on breast tissue, does not stimulate breast cell proliferation via PGRMC1 (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.[20]

Antiandrogen activity

NOMAC has significant weak or moderate antiandrogenic activity (5 to 20 times less than that of cyproterone acetate (a strong antiandrogen),[13][17] with approximately 12–31% of the RBA of testosterone for the androgen receptor).[6][15][21] It is said to be a stronger antiandrogen than dienogest (another commonly used progestin with antiandrogen activity), and may be useful in alleviating acne, seborrhea, and other androgen-dependent symptoms in women.[2][22]


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 drug 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 drug is eliminated via urine and feces.[1]


Nomegestrol was patented in 1975, and NOMAC, under the developmental code name TX-066, was first described in the literature in 1983.[4][23] It was developed by Theramex Laboratories, a pharmaceutical company in Monaco (a satellite country of France).[1] The drug was first introduced in Europe alone or in combination with estradiol under the respective brand names Lutenyl and Naemis[3] for the treatment of gynecological disorders and menopausal symptoms in 1986, and was subsequently developed and approved in 2011 in Europe as an oral contraceptive in combination with estradiol under the brand name Zoely.[1][7][8] As Zoely, NOMAC has been studied in over 4,000 women for contraception.[2]


Under the tentative trade name Uniplant, NOMAC was under development by Theramex as a 38 mg or 55 mg 4 cm Silastic (silicone-plastic) subdermal implant for one-year duration (75 ug/day or 100 μg/day release rate) contraception in Brazil from the 1990s and was extensively studied for this purpose in clinical trials.[24][25][26][27] 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.[27] In spite of this however, "[f]urther plans to make it available have been deferred by decision of the company holding the progestin patent"[28] and, although it continued to be investigated as late as 2006,[29] the implant ultimately never became commercially available.[30][31]

Society and culture


NOMAC (either alone (e.g., as Lutenyl) or in combination with estradiol (e.g., as Naemis))[3] is available for the treatment of gynecological disorders and menopausal symptoms in Argentina, Belgium, Brazil, Chile, France,[32][33] Georgia, Hong Kong, Indonesia, Italy, Lebanon, Lithuania, Malta, Monaco, the Netherlands, Peru, Poland, Portugal, Romania, Slovakia, Taiwan, Tunisia, Turkey, and Vietnam.[5][9] As a contraceptive (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.[9] It was expected that Zoely would become available in the United States in 2010,[34] but the FDA rejected the NDA for Zoely in 2011[35] and NOMAC ultimately has not been introduced in any form in this country.

See also


  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Lello, Stefano (2010). "Nomegestrol Acetate". Drugs. 70 (5): 541–559. doi:10.2165/11532130-000000000-00000. ISSN 0012-6667.
  2. 1 2 3 4 5 6 7 Ruan, Xiangyan; Seeger, Harald; Mueck, Alfred O. (2012). "The pharmacology of nomegestrol acetate". Maturitas. 71 (4): 345–353. doi:10.1016/j.maturitas.2012.01.007. ISSN 0378-5122.
  3. 1 2 3 4 5 6 Shields-Botella, J.; Chetrite, G.; Meschi, S.; Pasqualini, J.R. (2005). "Effect of nomegestrol acetate on estrogen biosynthesis and transformation in MCF-7 and T47-D breast cancer cells". The Journal of Steroid Biochemistry and Molecular Biology. 93 (1): 1–13. doi:10.1016/j.jsbmb.2004.11.004. ISSN 0960-0760. PMID 15748827.
  4. 1 2 3 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 883. ISBN 978-1-4757-2085-3.
  5. 1 2 3 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 747–. ISBN 978-3-88763-075-1.
  6. 1 2 3 4 Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1403–. ISBN 978-1-60913-345-0.
  7. 1 2 3 4 Yang, Lily P.H.; Plosker, Greg L. (2012). "Nomegestrol Acetate/Estradiol". Drugs. 72 (14): 1917–1928. doi:10.2165/11208180-000000000-00000. ISSN 0012-6667.
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  10. Bińkowska M, Woroń J (2015). "Progestogens in menopausal hormone therapy". Prz Menopauzalny. 14 (2): 134–43. doi:10.5114/pm.2015.52154. PMC 4498031Freely accessible. PMID 26327902.
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  12. Lyseng-Williamson, Katherine A.; Yang, Lily P. H.; Plosker, Greg L. (2012). "Nomegestrol acetate/estradiol: a guide to its use in oral contraception". Drugs & Therapy Perspectives. 29 (1): 1–6. doi:10.1007/s40267-012-0005-9. ISSN 1172-0360.
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  16. Jorge R. Pasqualini (17 July 2002). Breast Cancer: Prognosis, Treatment, and Prevention. CRC Press. pp. 224–. ISBN 978-0-203-90924-9.
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Further reading

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