Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Gedeon Richter Plc., Gyömrői út 19-21., 1103 Budapest, Hungary
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, natural and semisynthetic oestrogens, plain
ATC code: G03CA10
The active ingredient, synthetic estetrol, is chemically and biologically identical to endogenous estetrol that is produced during pregnancy by the human foetal liver.
Estetrol substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms, including vasomotor symptoms (VMS).
The clinical efficacy and safety of estetrol 14.2 mg and estetrol 18.9 mg were assessed in two multicentre phase 3 clinical trials (Trial 1 and Trial 2). Both trials had two parts: Part 1 (randomised, double-blind, placebo-controlled) mainly focused on efficacy and Part 2 (open-label, single arm) on safety.
The efficacy of estetrol for the relief of VMS was evaluated in postmenopausal women with moderate to severe VMS in Part 1 of Trials 1 and 2. In total, 628 hysterectomised (of whom 419 were treated with estetrol 14.2 mg or 18.9 mg and 209 were treated with placebo) and 591 non-hysterectomised (of whom 392 were treated with estetrol 14.2 mg or 18.9 mg and 199 were treated with placebo) were randomised.
The four co-primary efficacy endpoints for both trials were the change from baseline in the weekly frequency and mean severity of moderate to severe VMS at 4 weeks and 12 weeks.
Relief of menopausal symptoms was achieved during the first few weeks of treatment and maintained throughout the treatment period.
In both pivotal clinical trials, including non-hysterectomised women with at least 12 months since last menses and hysterectomised women, once daily oral doses of estetrol 14.2 mg and estetrol 18.9 mg showed statistically significant reduction in the weekly frequency of moderate to severe VMS at 4 weeks compared to placebo. The statistically significant reduction was maintained at 12 weeks of treatment.
Once daily oral doses of estetrol 18.9 mg showed statistically significant reduction in the severity of moderate to severe VMS at 4 weeks and 12 weeks compared to placebo. A statistically significant reduction in VMS severity was also observed with estetrol 14.2 mg at both time points in Trial 1 but not in Trial 2.
Results (post-hoc analyses) of the change in weekly frequency and mean severity of moderate to severe VMS from Trial 1 Part 1 and Trial 2 Part 1 are presented in Table 2 for estetrol 14.2 mg and Table 3 for estetrol 18.9 mg.
Table 2. Effect of estetrol 14.2 mg on the weekly frequency and mean severity of moderate to severe VMS at week 4 and week 12 – Non-hysterectomised women with at least 12 months since last menses and hysterectomised women (Trial 1, Part 1 and Trial 2, Part 1):
| Parameter | Trial 1, Part 1 | Trial 2, Part 1 | ||
| Estetrol 14.2 mg | Placebo | Estetrol 14.2 mg | Placebo | |
| N=200 | N=200 | N=185 | N=185 | |
| Frequency of VMS | ||||
| Baseline | ||||
| Mean (SD) | 78.54 (37.832) | 76.87 (35.327) | 80.32 (51.991) | 79.67 (41.013) |
| Change from baseline to week 4 | ||||
| LS Mean (SE) | -43.31 (2.984) | -32.17 (3.103) | -42.09 (2.736) | -32.38 (2.801) |
| LS Mean Difference vs. placebo (SE) | -11.14 (4.299) | - | -9.71 (3.916) | - |
| 95% CI | (-20.64, -1.65) | - | (-18.36, -1.05) | - |
| p-value vs. placebo | 0.0181 | - | 0.0249 | - |
| Change from baseline to week 12 | ||||
| LS Mean (SE) | -59.33 (3.098) | -41.81 (3.238) | -58.34 (2.806) | -45.01 (2.916) |
| LS Mean Difference vs. placebo (SE) | -17.52 (4.475) | - | -13.32 (4.047) | - |
| 95% CI | (-27.41, -7.64) | - | (-22.26, -4.38) | - |
| p-value vs. placebo | 0.0002 | - | 0.0020 | - |
| Severity of VMS | ||||
| Baseline | ||||
| Mean (SD) | 2.43 (0.280) | 2.38 (0.270) | 2.46 (0.284) | 2.47 (0.236) |
| Change from baseline to week 4 | ||||
| LS Mean (SE) | -0.65 (0.071) | -0.37 (0.073) | -0.42 (0.063) | -0.35 (0.065) |
| LS Mean Difference vs. placebo (SE) | -0.29 (0.102) | - | -0.08 (0.091) | - |
| 95% CI | (-0.51, -0.06) | - | (-0.28, 0.12) | - |
| p-value vs. placebo | 0.0096 | - | 0.5901 | - |
| Change from baseline to week 12 | ||||
| LS Mean (SE) | -1.25 (0.074) | -0.71 (0.077) | -0.73 (0.066) | -0.69 (0.068) |
| LS Mean Difference vs. placebo (SE) | -0.54 (0.107) | - | -0.04 (0.095) | - |
| 95% CI | (-0.78, -0.30) | - | (-0.25, 0.17) | - |
| p-value vs. placebo | <0.0001 | - | 0.8533 | - |
CI: confidence interval; LS Mean: least square mean change from baseline estimated from an MMRM model; MMRM: Mixed-effects Model for Repeated Measures; SD: standard deviation; SE: standard error
Table 3. Effect of estetrol 18.9 mg on the weekly frequency and mean severity of moderate to severe VMS at week 4 and week 12 – Non-hysterectomised women with at least 12 months since last menses and hysterectomised women (Trial 1, Part 1 and Trial 2, Part 1):
| Parameter | Trial 1, Part 1 | Trial 2, Part 1 | ||
| Estetrol 18.9 mg | Placebo | Estetrol 18.9 mg | Placebo | |
| N=197 | N=200 | N=186 | N=185 | |
| Frequency of VMS | ||||
| Baseline | ||||
| Mean (SD) | 82.32 (50.093) | 76.87 (35.327) | 79.69 (50.816) | 79.67 (41.013) |
| Change from baseline to week 4 | ||||
| LS Mean (SE) | -48.45 (2.852) | -32.17 (3.103) | -42.83 (2.699) | -32.38 (2.801) |
| LS Mean Difference vs. placebo (SE) | -16.28 (4.219) | - | -10.44 (3.889) | - |
| 95% CI | (-25.60, -6.96) | - | (-19.04, -1.85) | - |
| p-value vs. placebo | 0.0002 | - | 0.0138 | - |
| Change from baseline to week 12 | ||||
| LS Mean (SE) | -64.46 (2.984) | -41.81 (3.238) | -60.61 (2.789) | -45.01 (2.916) |
| LS Mean Difference vs. placebo (SE) | -22.65 (4.408) | - | -15.59 (4.035) | - |
| 95% CI | (-32.39, -12.92) | - | (-24.51, -6.67) | - |
| p-value vs. placebo | <0.0001 | - | 0.0002 | - |
| Severity of VMS | ||||
| Baseline | ||||
| Mean (SD) | 2.40 (0.273) | 2.38 (0.270) | 2.47 (0.223) | 2.47 (0.236) |
| Change from baseline to week 4 | ||||
| LS Mean (SE) | -0.69 (0.068) | -0.37 (0.073) | -0.61 (0.063) | -0.35 (0.065) |
| LS Mean Difference vs. placebo (SE) | -0.33 (0.100) | - | -0.26 (0.090) | - |
| 95% CI | (-0.55, -0.10) | - | (-0.46, -0.06) | - |
| p-value vs. placebo | 0.0022 | - | 0.0075 | - |
| Change from baseline to week 12 | ||||
| LS Mean (SE) | -1.36 (0.072) | -0.71 (0.077) | -1.12 (0.066) | -0.69 (0.068) |
| LS Mean Difference vs. placebo (SE) | -0.65 (0.106) | - | -0.43 (0.095) | - |
| 95% CI | (-0.89, -0.42) | - | (-0.64, -0.22) | - |
| p-value vs. placebo | <0.0001 | - | <0.0001 | - |
CI: confidence interval; LS Mean: least square mean change from baseline estimated from an MMRM model; MMRM: Mixed-effects Model for Repeated Measures; SD: standard deviation; SE: standard error
The endometrial safety of estetrol 18.9 mg, continuously combined with P4 100 mg was evaluated in 346 non-hysterectomised postmenopausal women in a 1-year open-label trial (Trial 1 Part 2), of whom 325 had an evaluable endometrial biopsy after 1 year. In the sub-population of women with at least 12 months since last menses, endometrial safety was evaluated in 316 women, of which 298 had an evaluable endometrial biopsy after 1 year.
During the clinical trial, assessments of endometrial biopsies taken at 12 months or at early trial discontinuation revealed 1 case of endometrial hyperplasia without atypia, no case of endometrial hyperplasia with atypia and no endometrial cancer (N=1/325, 0.3%; 2-sided 95% CI: 0.0 - 1.7%). In the post-hoc analysis of the sub-population of non-hysterectomised women with at least 12 months since last menses (n=298), the point estimate was 0.3% (2-sided 95% CI: 0.0 - 1.9%).
In Trial 1 Part 2, 853 non-hysterectomised women with at least 12 months since last menses received estetrol 18.9 mg with P4 100 mg continuously for up to 53 weeks. Absence of bleeding or spotting was seen in 37.8% of the women during months 10-12 treatment. Bleeding and/or spotting appeared in 77.2% of the women during the first three months of treatment and in 62.2% during months 10-12 of treatment.
Estetrol is rapidly absorbed after ingestion. After intake of estetrol at doses of 14.2 mg and 18.9 mg in tablet formulation, average peak plasma concentrations of 17.9 ng/mL and 17.3-20.75 ng/mL, respectively, are reached 0.47-0.63 hours after single ingestion. The extent of exposure to estetrol is similar irrespective of food intake. The maximum observed plasma concentration (Cmax) of estetrol is reduced by approximately 50% after food intake. The peak concentration of estetrol is reached sooner in fasted conditions than in fed conditions (median time of maximum observed plasma concentration (Tmax) 0.5 hours under fasted conditions compared to 1 hour under fed conditions).
Based on results of the mass balance study the bioavailability of estetrol was estimated at least 69%.
After multiple doses of estetrol 14.2 mg taken once daily for 14 days, the median Tmax,ss is approximately 0.5 hour. Steady state is achieved after 6 to 8 days. At steady state, the Cmax, the average concentration and the minimal concentration (trough level) are 16.69 ng/mL, 3.08 ng/mL and 1.42 ng/mL, respectively.
After multiple doses of estetrol 18.9 mg taken once daily for 8 days, the median Tmax,ss is approximately 0.5 hour. Steady state is achieved after 6 to 8 days. At steady state, the Cmax, the average concentration and the minimal concentration (trough level) are 19.6 ng/mL, 3.50 ng/mL and 1.59 ng/mL, respectively.
The pharmacokinetics of estetrol are characterized by a rapid distribution phase; it is distributed and probably reabsorbed by enterohepatic cycling during the first 18 hours after oral intake. The volume of distribution determined after oral administration of a single dose of 14.2 mg was high indicating that estetrol is widely distributed in tissues.
Estetrol does not bind to SHBG. Estetrol displayed moderate binding to human plasma proteins (45.5 to 50.4%). Estetrol is equally distributed between red blood cells and plasma.
In vitro studies indicated that estetrol is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Co-administration of drugs that affect the activity of P-gp and BCRP is however unlikely to result in a clinically relevant drug interaction with estetrol.
After oral administration, estetrol undergoes extensive phase 2 metabolism to form glucuronide and sulphate conjugates. The two main metabolites estetrol-3-glucuronide and estetrol-16-glucuronide have negligible oestrogenic activity. UGT2B7 is the dominant UGT isoform involved in the biotransformation of estetrol into a direct glucuronide. Estetrol undergoes sulfation, mainly by specific oestrogen sulfotransferase (SULT1E1).
The terminal elimination half-life (t1/2) of estetrol was observed to be around 24 hours both after single administration and under steady state conditions.
Following administration of a single oral solution of 15 mg [14C]-estetrol, approximately 69% of the total recovered radioactivity was detected in urine and 21.9% in faeces.
Estetrol plasma levels do not show any relevant deviation from dose-proportionality over a dose range of 4.7 mg up to 94.4 mg (single administration).
Steady-state is achieved after 6 to 8 days. After once daily repeated oral administration of estetrol 14.2 mg or 18.9 mg, the maximum plasma concentrations of estetrol are about 16.69 ng/mL and 19.60 ng/m, respectively, and are reached 0.18-2 hours after dosing. Average plasma concentrations are 3.08 ng/mL and 3.50 ng/mL, respectively. The accumulation is very limited with daily area under the curve (AUC) at steady-state 60% larger than after a single dose and no observed increase in Cmax.
A study has been performed with a single oral dose of estetrol 18.9 mg administered in female subjects with normal hepatic function, mild hepatic impairment (Child-Pugh class A), moderate hepatic impairment (Child-Pugh class B), and severe hepatic impairment (Child-Pugh class C).
The results show that Cmax and area AUCinf ratios for estetrol were ~1.7-fold and ~1.1-fold, respectively, in mild hepatic impairment versus subjects with normal hepatic function, ~1.9-fold and ~1-fold, respectively, in moderate hepatic impairment versus subjects with normal hepatic function, and ~5.4-fold and ~1.9-fold, respectively, in severe hepatic impairment versus subjects with normal hepatic function (see section 4.2).
A study to evaluate the effect of renal disease on pharmacokinetics of estetrol was performed with a single oral dose of estetrol 18.9 mg administered in female subjects with normal renal function, mild renal impairment (absolute glomerular filtration rate (GFR <90 to ≥60 mL/min), moderate renal impairment (GFR <60 to ≥30 mL/min) and severe renal impairment (GFR <30 mL/min).
Cmax and AUCinf for estetrol were ~1.1-fold and ~1.7-fold, respectively, in mild renal impairment versus subjects with normal renal function; ~1.8-fold and ~2.3-fold, respectively, in moderate renal impairment versus subjects with normal renal function, and ~1.5-fold and ~2.3-fold, respectively, in severe renal impairment versus subjects with normal renal function.
Renal clearance (CLr) was decreased by 20% in the group with mild renal impairment, 40% in the group with moderate renal impairment, and 71% in the group with severe renal impairment compared to the group with normal renal function.
The study results indicate that the increase of estetrol plasma exposure in subjects with moderate and severe renal impairment compared to subjects with a normal renal function could be of clinical relevance (see section 4.2).
No clinically relevant differences in the pharmacokinetics of estetrol between Japanese and Caucasian women have been observed after single dose administration of estetrol 14.2 mg.
Repeated dose toxicity studies with estetrol have indicated expected oestrogenic effects. In particular, reproduction toxicity studies revealed embryonic and foetotoxic effects in animals which are considered as species specific.
Estetrol is not considered to be genotoxic. However, it is known that due to their hormonal action, sex steroids can promote the growth of certain hormone-dependent tissues and tumours.
Environmental risk assessment studies have shown that estetrol may pose a risk to the aquatic environment and to the groundwater compartment.
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