Nomegestrol acetate

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Nomegestrol acetate
Nomegestrol acetate.svg
Nomegestrol acetate molecule ball.png
Clinical data
Trade names Alone: 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 class Progestogen; Progestin; Progestogen ester; Steroidal antiandrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 63% [1]
Protein binding 97.5–98.0% (to albumin) [1]
Metabolism Liver (by hydroxylation via CYP3A3, CYP3A4, CYP2A6) [1]
Metabolites Six main metabolites, all essentially inactive [1]
Elimination half-life ~50 hours (range 30–80 hours) [1] [2]
Excretion Urine, 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 InfoCard 100.055.781 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H30O4
Molar mass 370.489 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]

Contents

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]

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 PR Tooltip Progesterone receptor AR Tooltip Androgen receptor ER Tooltip Estrogen receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Nomegestrol acetate1254206000
Megestrol acetate 655030000
Progesterone 500010100036
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip 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-HSD Tooltip 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 ER Tooltip 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 PGRMC1 Tooltip 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 INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip 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. Nomegestrol acetate availability.png
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 FDA Tooltip Food and Drug Administration rejected the NDA Tooltip 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]

References

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  55. ↑ "Nomegestrol oral". AdisInsight. Springer Nature Switzerland AG.
  56. ↑ "Estradiol/Nomegestrol intravaginal ring". AdisInsight. Springer Nature Switzerland AG.
  57. ↑ "Estradiol/Nomegestrol continuous". AdisInsight. Springer Nature Switzerland AG.

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