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| Clinical data | |
|---|---|
| Trade names | Alone: Lutenyl WithE2: Naemis, Zoely |
| Other names | NOMAC; 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 class | Progestogen;Progestin;Progestogen ester;Steroidal antiandrogen |
| ATC code | |
| Legal status | |
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| Pharmacokinetic data | |
| Bioavailability | 63%[1] |
| Protein binding | 97.5–98.0% (toalbumin)[1] |
| Metabolism | Liver (byhydroxylation viaCYP3A3,CYP3A4,CYP2A6)[1] |
| Metabolites | Six mainmetabolites, all essentially inactive[1] |
| Eliminationhalf-life | ~50 hours (range 30–80 hours)[1][2] |
| Excretion | Urine,feces[1] |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
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| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.055.781 |
| Chemical and physical data | |
| Formula | C23H30O4 |
| Molar mass | 370.489 g·mol−1 |
| 3D model (JSmol) | |
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Nomegestrol acetate (NOMAC), sold under the brand namesLutenyl andZoely among others, is aprogestin medication which is used inbirth control pills,menopausal hormone therapy, and for the treatment ofgynecological disorders.[3][1][4][5][6][7] It is available both alone and in combination with anestrogen.[8][9] NOMAC is takenby mouth.[3] Abirth control implant for placementunder the skin was also developed but ultimately was not marketed.[10][11][12][13]
Side effects of NOMAC includemenstrual irregularities,headaches,nausea,breast tenderness, and others.[1][14] NOMAC is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[3] It has someantiandrogenic activity and no other importanthormonal 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, inEurope 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 theUnited States orCanada.[8][1][17][18]
NOMAC is used alone in the treatment ofgynecological disorders includingmenstrual disturbances (e.g.,dysmenorrhea,menorrhagia,oligomenorrhea,polymenorrhea,amenorrhea),vaginal bleeding,breast pain, andpremenstrual syndrome and inmenopausal hormone therapy.[1][5][14] It is used in combination withestradiol as abirth control pill and in menopausal hormone therapy.[1][17][18] NOMAC-only tablets are also used as a form ofprogestogen-only birth control, although they are not specifically licensed as such.[20]
NOMAC is available both alone and in combination with estrogens.[8][9] The following formulations are available:[8][9]
The availability of these formulations differs by country.[8]
Because NOMAC ismetabolized by theliver,hepatic impairment can result in an accumulation of the medication.[21]
Theside 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 includemenstrual irregularities (e.g., abnormal bleeding or spotting),headache,nausea,breast tenderness, andweight 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]
There have been no reports of seriousadverse effects due tooverdose 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 includenausea,vomiting, and, in young girls, slightvaginal bleeding.[7] There is noantidote for NOMAC overdose and treatment of overdose should be based onsymptoms.[7]
Themetabolism of NOMAC is dependent onCYP3A4, soinhibitors andinducers of this enzyme such asketoconazole andrifampicin, respectively, as well as someanticonvulsants, may pose a clinically significantdrug interaction with NOMAC.[1][2] (For a list of CYP3A4 inhibitors and inducers, seehere.)
NOMAC hasprogestogenic activity,antigonadotropic effects,antiandrogenic activity, and no other importanthormonal activity.[3]
| 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 (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,estradiol for theERTooltip estrogen receptor,dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources:[3] | ||||||||
NOMAC is apotent and pureprogestogen, acting as a selective, high-affinityfull agonist of theprogesterone receptor (PR) (Ki = 3 nM, 67–303% of therelative binding affinity ofprogesterone),[29] and is said to have higher potency and substantially improvedselectivity for the PR relative tomedroxyprogesterone acetate (the 6-hydrogenated or non-6-7-double bondedanalogue ofmegestrol acetate and the most widely used progestin).[4][30][31] In accordance, NOMAC is a potentantigonadotropin and exhibits noandrogenic,estrogenic,[32]glucocorticoid, orantimineralocorticoid activity,[1] but does possess someantiandrogenic activity.[29][33] Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic andantiestrogenic effects when administered at sufficiently high doses.[1]
Like many otherprogestogens,[34][35] NOMAC has been assessed and foundin vitro to inhibit the conversion ofestrone sulfate toestrone (via inhibition ofsteroid sulfatase) and estrone to estradiol (via inhibition of17β-HSDTooltip 17β-hydroxysteroid dehydrogenase) at high concentrations (0.5–50 μM) and to stimulate the conversion of estrone into estrone sulfate (via activation ofestrogen sulfotransferase activity) at low concentrations (0.05–0.5 μM), whilst not affectingaromatase 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 antagonistmifepristone (RU-486).[5] Although the clinical implications of these actions are unclear and they have yet to be confirmedin vivo or assessed inclinical studies, it has been suggested that NOMAC and certain other progestins may be useful in the treatment ofERTooltip estrogen receptor-positivebreast cancer by decreasing levels ofestrogens 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 viaPGRMC1Tooltip progesterone receptor membrane component 1 (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.[36]
Theovulation-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 ofpregnancy with one missed pill of Zoely or even with two missed pills during days 8 to 17 of themenstrual cycle.[2]
NOMAC acts as anantagonist of theandrogen receptor (AR), with approximately 12 to 31% of therelative binding affinity oftestosterone for the AR and 42% of the affinity ofmetribolone 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 ofcyproterone acetate depending on the source.[29][33][3][39][40][41] The antiandrogenic activity of NOMAC may be useful in helping to alleviateacne,seborrhea, and otherandrogen-dependent symptoms in women.[2][41]
Certain progestins have been found to stimulate theproliferation ofMCF-7breast cancercellsin vitro, an action that is independent of the classical PRs and is instead mediated via theprogesterone 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 inclinical studies.[43]
NOMAC is well-absorbed, with an oralbioavailability of 63%.[1] It is 97.5 to 98%protein-bound, toalbumin, and does not bind tosex hormone-binding globulin orcorticosteroid-binding globulin.[1] The medication ismetabolizedhepatically viahydroxylation by theenzymesCYP3A3,CYP3A4, andCYP2A6.[1] It has six mainmetabolites, all of which have no or minimal progestogenic activity.[1] Theelimination 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 iseliminated viaurine andfeces.[1]
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 asyntheticnorpregnanesteroid and aderivative ofprogesterone belonging to the19-norprogesterone and17α-hydroxyprogesterone groups.[15] NOMAC is the C17αacetateester ofnomegestrol and the 19-demethylated (or 19-nor)analogue ofmegestrol acetate, and can also be referred to as 19-normegestrol acetate.[15][4]
Nomegestrol was patented in 1975, and NOMAC, under the developmental code nameTX-066, was first described in the literature in 1983.[15][16] It was developed by Theramex Laboratories, apharmaceutical company inMonaco (a satellite country ofFrance).[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]
Nomegestrol acetate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name.[15][19][8] It is also known by its former developmental code nameTX-066.[15][19][8]
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]
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 inArgentina,Belgium,Brazil,Chile,France,[44][45]Georgia,Hong Kong,Indonesia,Italy,Lebanon,Lithuania,Malta,Monaco, theNetherlands,Peru,Poland,Portugal,Romania,Slovakia,Taiwan,Tunisia,Turkey, andVietnam.[8][46][47][19] As a component of birth control pills with estradiol (under the brand name Zoely), NOMAC is available inArgentina,Australia,Austria,Belgium,Chile,Colombia,Croatia,Costa Rica,Denmark, theDominican Republic,El Salvador,Finland,France,Germany,Guatemala,Honduras,Hungary,Ireland,Israel,Italy,Latvia,Lithuania,Malaysia,Monaco, theNetherlands,New Zealand,Nicaragua,Norway,Panama,Poland,Portugal,Russia,Spain,Slovakia,Sweden,Switzerland, and theUnited Kingdom.[8][46][47][19] It was expected that Zoely would become available in theUnited States in 2010,[48] but theFDATooltip Food and Drug Administration rejected theNDATooltip New Drug Application for Zoely in 2011[49] and NOMAC ultimately has not been introduced in any form in this country.[50]
Under the tentative brand name Uniplant, NOMAC was under development by Theramex as a 38 mg or 55 mg 4 cmSilastic (silicone-plastic)subcutaneousbirth control implant of one-year duration (75 ug/day or 100 μg/day release rate) inBrazil from the 1990s and was extensively studied for this purpose inclinical 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 ofbreast cancer and for use as aprogestogen-only pill for birth control but did not complete development for these indications.[55] An estradiol and NOMACvaginal ring was under development for use in birth control and to treatdysmenorrhea 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 ofpostmenopausal osteoporosis but did not complete development.[57]