Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Theramex Ireland Limited, 3rd Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1, D01 YE64, Ireland
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens and estrogens, fixed combinations
ATC code: G03AA14
Nomegestrol acetate is a highly selective progestogen derived from the naturally occurring steroid hormone, progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptor and has an anti-gonadotropic activity, a progesterone receptor-mediated anti-oestrogenic activity, a moderate anti-androgenic activity, and is devoid of any oestrogenic, androgenic, glucocorticoid or mineralocorticoid activity.
The oestrogen contained in Zoely is 17β-estradiol, an oestrogen identical to the endogenous human 17β-estradiol.
The contraceptive effect of Zoely is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
In two randomised, open-label, comparative efficacy-safety trials, more than 3,200 women have been treated for up to 13 consecutive cycles with Zoely and more than 1,000 women with drospirenone 3 mg – ethinylestradiol 30 μg (21/7 regimen).
In the Zoely group, acne was reported by 15.4% of the women (versus 7.9% in the comparator group), weight increased was reported by 8.6% of the women (versus 5.7% in the comparator group), and abnormal withdrawal bleeding (predominantly absence of withdrawal bleeding) was reported by 10.5% of the women (versus 0.5% in the comparator group).
In the clinical trial performed with Zoely in the European Union the following Pearl Indices for the age class 18-35 years were calculated: Method failure: 0.40 (upper limit 95% confidence interval 1.03). Method and user failure: 0.38 (upper limit 95% confidence interval 0.97).
In the clinical trial performed with Zoely in the United States the following Pearl Indices for the age class 18-35 years were calculated:
Method failure: 1.22 (upper limit 95% confidence interval 2.18).
Method and user failure: 1.16 (upper limit 95% confidence interval 2.08).
In a randomised, open label trial, 32 women were treated for 6 cycles with Zoely. After discontinuation of Zoely, return to ovulation in the first 28 days after last tablet intake was observed in 79% of the women.
Endometrial histology was investigated in a subgroup of women (n=32) in one clinical study after 13 cycles of treatment. There were no abnormal results.
No data on efficacy and safety are available in adolescents below 18 years. Available pharmacokinetic data are described in section 5.2.
Orally administered nomegestrol acetate is rapidly absorbed. Maximum plasma concentrations of nomegestrol acetate of about 7 ng/mL are reached at 2 h after single administration. The absolute bioavailability of nomegestrol acetate after a single dose is 63%. No clinically relevant effect of food was observed on the bioavailability of nomegestrol acetate.
Nomegestrol acetate is extensively bound to albumin (97-98%), but does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). The apparent volume of distribution of nomegestrol acetate at steady-state is 1,645 576 L.
Nomegestrol acetate is metabolized into several inactive hydroxylated metabolites by liver cytochrome P450 enzymes, mainly CYP3A4 and CYP3A5 with possible contribution of CYP2C19 and CYP2C8. Nomegestrol acetate and its hydroxylated metabolites undergo extensive phase 2 metabolism to form glucuronide- and sulphate conjugates. The apparent clearance at steady state is 26 L/h.
The elimination half-life (t½) is 46 h (ranging from 28-83 h) at steady state. The elimination half-life of metabolites was not determined.
Nomegestrol acetate is excreted via urine and faeces. Approximately 80% of the dose is excreted in urine and faeces within 4 days. Excretion of nomegestrol acetate was nearly complete after 10 days and amounts excreted were higher in faeces than in urine.
Dose-linearity was observed in the range 0.625-5 mg (assessed in fertile and post-menopausal women).
The pharmacokinetics of nomegestrol acetate are not influenced by SHBG. Steady-state is achieved after 5 days. Maximum plasma concentrations of nomegestrol acetate of about 12 ng/mL are reached 1.5 h after dosing. Average steady state plasma concentrations are 4 ng/mL.
Nomegestrol acetate causes in vitro no notable induction or inhibition of any cytochrome P450 enzymes and has no clinically relevant interaction with the P-gp transporter.
Estradiol is subject to a substantial first-pass effect after oral administration. The absolute bioavailability is about 1%. No clinically relevant effect of food was observed on the bioavailability of estradiol.
The distribution of exogenous and endogenous estradiol is similar. Oestrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound.
Oral exogenous estradiol is extensively metabolized. The metabolism of exogenous and endogenous estradiol is similar. Estradiol is rapidly transformed in the gut and the liver in several metabolites, mainly estrone, which are subsequently conjugated and undergo entero-hepatic circulation. There is a dynamic equilibrium between estradiol, estrone and estrone-Sulfate due to various enzymatic activities including estradiol-dehydrogenases, sulfotransferases and aryl sulfatases. Oxidation of estrone and estradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9.
Estradiol is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation, a large circulating pool of oestrogen sulfates and glucuronides is present. This results in a highly variable baseline-corrected elimination half-life of estradiol, which is calculated to be 3.6 ± 1.5 h, after intravenous administration.
Maximum serum concentrations of estradiol are about 90 pg/mL and are reached 6 h after dosing. Average serum concentrations are 50 pg/mL and these estradiol levels correspond with the early and late phase of a woman’s menstrual cycle.
No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of Zoely.
No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Zoely. However, steroid hormones may be poorly metabolized in women with impaired liver function.
No formal studies were performed to assess pharmacokinetics in ethnic groups.
The pharmacokinetics of nomegestrol acetate (primary objective) after single oral dosing of Zoely in healthy postmenarcheal female adolescents and adult subjects were similar. However, after single oral dosing, for the estradiol component (secondary objective), the exposure was 36% lower in adolescents versus adult subjects. The clinical relevance of this result is unknown.
Repeated dose toxicity studies with estradiol, nomegestrol acetate or combination have indicated expected oestrogenic and gestagen effects.
Reproductive toxicity studies performed with the combination have shown foetotoxicity which is consistent with estradiol exposure.
Genotoxicity and carcinogenicity studies were not conducted with the combination. Nomegestrol acetate is not genotoxic.
However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.
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