1. NAME OF THE MEDICINAL PRODUCT
Zoely 2.5 mg/1.5 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
White active film-coated tablets: Each film-coated tablet contains 2.5 mg nomegestrol acetate and
1.5 mg estradiol (as hemihydrate).
Yellow placebo film-coated tablets: The tablet does not contain active substances.
Each white active film-coated tablet contains 57.71 mg of lactose monohydrate.
Each yellow placebo film-coated tablet contains 61.76 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Active film-coated tablets: white, round and coded ‘ne’ on both sides.
Placebo film-coated tablets: yellow, round and coded ‘p’ on both sides.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
One tablet is to be taken daily for 28 consecutive days. Each pack starts with 24 white active tablets,
followed by 4 yellow placebo tablets. A subsequent pack is started immediately after finishing the
previous pack, without a break in daily tablet intake and irrespective of presence or absence of
withdrawal bleeding. Withdrawal bleeding usually starts on day 2-3 after intake of the last white tablet
and may not have finished before the next pack is started. See ‘Cycle control’ in section 4.4.
Although data in renal impaired patients are not available, renal impairment is unlikely to affect the
elimination of nomegestrol acetate and estradiol.
No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism
of steroid hormones might be impaired in patients with severe hepatic disease, the use of Zoely in
these women is not indicated as long as liver function values have not returned to normal (see section
Method of administration
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-estrogenic activity, a
moderate anti-androgenic activity, and is devoid of any estrogenic, androgenic, glucocorticoid or
The estrogen contained in Zoely is 17β-estradiol, a natural estrogen identical to the endogenous human
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 randomized, 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: 12
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 randomized, 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.
5.2 Pharmacokinetic properties
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
The elimination half-life (t1/2) 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 feces. Approximately 80 % of the dose is excreted in
urine and feces within 4 days. Excretion of nomegestrol acetate was nearly complete after 10 days and
amounts excreted were higher in feces than in urine.
Dose-linearity was observed in the range 0.625-5 mg (assessed in fertile and post-menopausal
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.
Drug drug interactions
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. 13
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
The distribution of exogenous and endogenous estradiol is similar. Estrogens 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 estrogen 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
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.
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.
Effect of renal impairment
No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of Zoely.
Effect of hepatic impairment
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.
5.3 Preclinical safety data
Repeat dose toxicity studies with estradiol, nomegestrol acetate or combination have indicated
expected estrogenic and gestagen effects.
Reproductive toxicity studies performed with the combination have shown foetotoxicity which is
consistent with estradiol exposure. 14
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 hormonedependent tissues and tumours.
Other contraceptive pills: