Nomegestrol acetate

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 HRT for menopause. It is also used as an oral contraceptive with estradiol (as Zoely).

Hepatic impairment

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

Side effects

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

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. (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) (K_i = 3 nM, 67–303% of the RBA of progesterone), 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). In accordance, NOMAC is a potent antigonadotropin and exhibits no androgenic, estrogenic, glucocorticoid, or antimineralocorticoid activity, but does possess some antiandrogenic activity (see below). Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and antiestrogenic effects when administered at sufficiently high dosages.

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.

Inhibition of estrogen biosynthesis in breast tissue

Like many other progestogens, 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). 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). 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. 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.

Antiandrogen activity

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

Pharmacokinetics

NOMAC is well-absorbed, with an oral bioavailability of 63%. It is 97.5 to 98% protein-bound, to albumin, and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin. The drug is metabolized hepatically via hydroxylation by the enzymes CYP3A3, CYP3A4, and CYP2A6. It has six main metabolites, all of which have no or minimal progestogenic activity. The elimination half-life of NOMAC is approximately 50 hours, with a range of 30 to 80 hours. Steady-state concentrations of NOMAC are achieved after five days of repeated administration. 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. The drug is eliminated via urine and feces.

Chemistry

NOMAC is a norpregnane steroid and a derivative of progesterone belonging to the 19-norprogesterone and 17α-hydroxyprogesterone groups. It is also known as 17α-acetoxy-6-dehydro-6-methyl-19-norprogesterone or as 17α-acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione. 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.

History

Nomegestrol was patented in 1975, and NOMAC, under the developmental code name TX-066, was first described in the literature in 1983. It was developed by Theramex Laboratories, a pharmaceutical company in Monaco (a satellite country of France). The drug was first introduced in Europe alone or in combination with estradiol under the respective brand names Lutenyl and Naemis 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. As Zoely, NOMAC has been studied in over 4,000 women for contraception.

Uniplant

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. 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. In spite of this however, "[f]urther plans to make it available have been deferred by decision of the company holding the progestin patent" and, although it continued to be investigated as late as 2006, the implant ultimately never became commercially available.

Generic name

Nomegestrol acetate is the INN, USAN, and BAN of NOMAC.

Availability

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