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. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed. Side effects of NOMAC include menstrual irregularities, headaches, nausea, breast tenderness, and others. NOMAC is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has some antiandrogenic activity and no other important hormonal activity. Nomegestrol, a related compound, was patented in 1975, and NOMAC was described in 1983. NOMAC was first introduced for medical use, for the treatment of gynecological disorders and in menopausal hormone therapy, in Europe in 1986. It was subsequently approved in Europe in 2011 as a component of birth control pills. NOMAC is available widely throughout the world. It is not available in the United States or Canada.
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. It is used in combination with estradiol as a birth control pill and in menopausal hormone therapy. NOMAC-only tablets are also used as a form of progestogen-only birth control, although they are not specifically licensed as such.
Available forms NOMAC is available both alone and in combination with estrogens. The following formulations are available:
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.
Contraindications Because NOMAC is metabolized by the liver, hepatic impairment can result in an accumulation of the medication.
Side effects The side effects of NOMAC are similar to those of other progestogens. It is well tolerated and often produces no side effects. Possible side effects of NOMAC include menstrual irregularities (e.g., abnormal bleeding or spotting), headache, nausea, breast tenderness, and weight gain. However, body weight is generally unchanged. Rarely, meningiomas have been reported in association with NOMAC.
Overdose There have been no reports of serious adverse effects due to overdose of NOMAC. 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. Symptoms of NOMAC and estradiol overdose might include nausea, vomiting, and, in young girls, slight vaginal bleeding. There is no antidote for NOMAC overdose and treatment of overdose should be based on symptoms.
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.)
Pharmacology
Pharmacodynamics NOMAC has progestogenic activity, antigonadotropic effects, antiandrogenic activity, and no other important hormonal activity.
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), 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. Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and antiestrogenic effects when administered at sufficiently high doses. 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-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). 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 ERTooltip estrogen receptor-positive breast cancer by decreasing levels of estrogens 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 PGRMC1Tooltip progesterone receptor membrane component 1 (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.
Antigonadotropic effects The ovulation-inhibiting dosage of NOMAC is 1.5 to 5 mg/day. 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.
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