Frequently asked questions about NEXTSTELLIS^®

Produced during pregnancy, E4 is found at high levels in maternal fetal circulation.³¹ For pharmaceutical use, E4 originates from a plant source and offers a distinct pharmacologic profile compared to other contraceptive estrogens.^1,17,35 E4’s unique structure and selective action in tissues means it can be considered a low impact estrogen because it has low impact on haemostatic and metabolic markers including SHBG (sex hormone binding globulin) and TBG (thyroid binding globulin).^2,6

In vivo, pharmacodynamic (PD) studies showed that E4 acts as an estrogen agonist on the brain, vagina, uterus, endometrium, and bones.^6,13-16

E4 has markedly different biological activity, pharmacodynamic profile, and pharmacokinetic properties compared with estradiol (E2) and EE.³³ Therefore, its dosing cannot be directly compared to other estrogens. E4 can be considered much less potent (12,000 times lower) than EE on the estrogen receptors^.6,9,13 The selective activity and binding characteristics mean that E4 can be considered as a low-impact estrogen compared with EE.^2,6

The lowest effective dose of E4 and DRSP was established in Phase 2 dose-finding studies and validated in the Phase 3 studies that were the basis of its approval.^21,27,33

E4 — the estrogen component in NEXTSTELLIS — was studied in combination with drospirenone or levonorgestrel. Both progestins demonstrated adequate safety and efficacy. However, differences emerged in Phase 2 studies that evaluated bleeding patterns and patient-reported overall satisfaction scores.^21,27,33

Drospirenone was identified as the optimal progestin to combine with E4 as it is the progestin that most closely matches the body’s natural progesterone.¹

NEXTSTELLIS combines drospirenone (DRSP), a proven progestin, with a new low impact* estrogen, estetrol (E4).^1,2

NEXTSTELLIS is the first and only contraceptive pill containing E4. E4 is produced naturally by the foetus during pregnancy. In NEXTSTELLIS the E4 originates from a plant source, to match the body’s naturally occurring E4.^31-35

E4 works differently in the body than other estrogens:

• It has selective action in the tissues where you want it to work for contraceptive efficacy and cycle control, with less impact where you want minimal activity, like on breast tissue and the liver.^2,6,17
• E4 doesn’t reconvert back into E1, E2, or E3; nor does it produce carcinogenic metabolites unlike the estrogens available in other contraceptive pills.^1,2,4

*based on its selectivity, potency, pharmacokinetics, mechanism of action, and impact on the liver.

The efficacy of NEXTSTELLIS assessed by life-table analyses in the Phase 3 studies was 99.6% in the European study for women aged 18-35 years and in the Northern American study 98% for women aged 16-35 years for up to one year of treatment.^7,25

In clinical trials, NEXTSTELLIS demonstrated a highly predictable bleeding profile. Unscheduled bleeding with NEXTSTELLIS occurred in <2% of women and the average duration of spotting or bleeding episodes was <1 day, with only 1% of women discontinuing treatment in the studies due to metrorrhagia.¹

In the Phase 3 studies, the Pearl Index for NEXTSTELLIS in the European study was 0.47 and in the Northern American study was 2.65. The higher Pearl Index for US is comparable to other recently launched contraceptives. For example, SLINDA was 2.91.³⁷

Of the 3,790 patients evaluated for safety across the full clinical program, NEXTSTELLIS was well-tolerated and without unexpected safety concerns for a combined oral contraceptive in terms of the frequency, nature and severity of treatment emergent adverse events (TEAEs). TEAEs were most commonly found in the system organ class (SOC) Infections and Infestations, with 21.2% of subjects having a TEAE in this SOC, but the vast majority of these TEAEs were not related to NEXTSTELLIS.¹

TGA approved Product Information for NEXTSTELLIS includes precautions for women over 35 years who are smokers. This is consistent with product labeling for all combined hormonal contraceptives.^1,28

In the Phase 3 clinical studies of NEXTSTELLIS, with a combined safety population of 3,632, a VTE occurred in 1 patient, for an annual incidence rate of 3.66 per 10,000 women-years.¹ The annual risk for VTE in women on any COC is estimated at 3 to 9 per 10,000 women-years. This estimate is within the reference range of the FDA and EMA for non-pregnant, non-COC users (1-5 / 10,000 women years) and at the lower end of that of COC-users (3-9 / 10,000 women years).¹ Longer-term studies will be needed to determine if there are differences in VTE risk with NEXTSTELLIS compared with other COCs.

E4 has a low estrogenic impact on the liver.^1,2

In Phase 2 clinical studies NEXTSTELLIS has less effect than EE-based contraceptives on lipid parameters. The limited impact of NEXTSTELLIS on lipid metabolism was confirmed in two Phase 3 trials, where no statistically significant changes from baseline were observed for LDL-C, HDL-C, total cholesterol, and triglycerides during treatment.^1,23

In addition, a Phase 2 safety study was undertaken to analyse the effects of NEXTSTELLIS on liver proteins which resulted in a less pronounced effect on sex hormone binding globulin (SHBG), cortisol binding globulin (CBG), thyroxin binding globulin (TBG) and angiotensinogen compared to other combined oral contraceptive combinations studied (EE/DRSP and EE/LNG).^26,27

NEXTSTELLIS is a monophasic regimen with an approved regimen of 24 active and 4 placebo pills per 28-day cycle pack.¹

No, it has not been approved for continuous cycling.¹

NEXTSTELLIS (Australian TGA Approved Product) contains 15 mg of estetrol monohydrate which is equivalent to 14.2 mg estetrol (E4).^1,28 Clinical studies refer to 15 mg estetrol monohydrate as the dose for simplicity which contains the same amount as approved in the Australian product (and rest of the world)^3,5,10

NEXSTELLIS is commercially available in Australia from 1 August 2022.

NEXTSTELLIS has been approved in Canada¹⁹ (March 2021), USA¹⁰ (April 2021) and in Europe (May 2021). In Europe there are two brands, DROVELIS³ and LYDISILKA⁵. These brands are identical in formulation to NEXTSTELLIS and contain E4 14.2 mg/DRSP 3 mg.