It gives women more choice, but is it safer or more natural?

Approved by the TGA in late 2021, the combined oral contraceptive pill Nextstellis® (estetrol 14.2 mg/drospirenone 3 mg) was PBS-listed on October 1. Here’s what you need to know.

Is it natural?

Nextstellis has been billed in some quarters as having a ‘natural’ oestrogen, but sexual health physician Dr Terri Foran, a conjoint senior lecturer in the School of Women’s and Children’s Health at UNSW, prefers to use another word. Like estradiol and estradiol valerate, estetrol is a body-identical oestrogen, she says.

Estetrol is produced in the fetal liver, she explains. “So this particular oestrogen only circulates in a woman’s body when she is pregnant.”

The estetrol in Nexstellis is a body identical oestrogen derived from a plant source.

It’s important to remember that the main contraceptive effect of COCPs actually comes from the progestogen component. In COCPs, body-identical oestrogens are always paired with synthetic progestogens, Dr Foran adds.

“And the reason is that body-identical progesterone, which we do see in some of the menopausal hormone therapies we have available, is not reliably contraceptive.”

Nextstellis comes in a pack containing 24 active and four inert tablets.

Is it safer than other COCPs?

In its submission to the Pharmaceutical Board Advisory Committee (PBAC), Nextstellis’s sponsors (Mayne Pharma International) said it has a lower longer-term risk of VTE, MI and stroke than ethinylestradiol/levonorgestrel effect of COCPs and ethinylestradiol/drospirenone.

But the PBAC said there was insufficient evidence to support these claims, noting there were no head-to-head studies. Rather, they used modelling based on surrogate biomarkers associated with VTE, MI and stroke risk (such as haemostasis markers, lipids, and glucose levels) from studies that did not include Nextstellis, as well as a phase II, open-label, single-centre study—which they said demonstrated “a high risk of bias”.

The PBAC concluded that “the claim of superior comparative safety was not adequately supported by the data.”

However, only time will tell for sure, Dr Foran says, noting it took about 20 years to get good data on the older COCPs.

“And that’s because things like clots in the legs and lungs are relatively rare in the age group of women who are using the pill,” she says.

Body-identical oestrogens may have fewer side effects

However, it makes physiological sense that newer pills containing body-identical oestrogens may have fewer serious long-term side effects, she adds.

“It is possible that because they’re more like our own hormones, they may have less effect on things like clotting factors and cardiovascular risk. At the moment though, we can’t put hand-on-heart and promise those benefits to our patients because these body-identical pills are relatively new. To get any reliable scientific evidence on that, you need millions of women to be taking them for a long period of time. But certainly, some of the features of these body-identical oestrogens are promising.”

They may also have fewer annoying side effects, such as fluid retention and headaches—which unfortunately are not uncommon in women who take older synthetic oestrogen pills, Dr Foran says.

Who is it suitable for?

The PBAC noted Nextstellis’s contraceptive efficacy is non-inferior to that of other listed COCPs.

The main benefit of the PBS listing is that it gives women more choice, Dr Foran says.

Nextstellis is a suitable first-line option if a COCP is appropriate—and may be particularly worth trying if women have had issues with other COCPs, she says.

“Having the ability to say to someone, well, this is something that’s different to the other pills you’ve been on before, and you may find that it suits you—I think that’s a bonus.”

“You might think of it if you get someone who might be older, for example, and says, ‘I’ve tried the pill before, and I’ve had side effects, and then I couldn’t use it. But I’m sick of all this bleeding, because I’m now 42 and my periods are heavier.’ So you can bring it up as one of the options if there are no contraindications to its use.”

“There are of course other options for her, such as a hormonal IUD, a contraceptive implant or a progestogen-only pill. But some women prefer combined oral contraception, especially if it has secondary benefits or if they wish to reduce the number of withdrawal bleeds experienced.”

That’s because Nextstellis, like most other COCPs, can be used off-label to manipulate cycles by running packets together, she adds.

Are there any caveats?

Nextstellis carries the same precautions and contraindications as other COCPs, Dr Foran says.

It should be avoided in women who’ve had a bad reaction to either of the active ingredients in the past, she adds, noting this is rare.

Safety and efficacy of Nexstellis has not been evaluated in women with a BMI of ≥ 35, according to the product information. A prospective open-label study which had 1,524 participants overall, including around 350 women whose BMI was between 30 and 35, found no difference in safety or efficacy based on BMI.

Key takeaways:

• Estetrol is a type of oestrogen naturally produced in the fetal liver. The estetrol in Nexstellis is a body identical oestrogen derived from a plant source.
• It has non-inferior contraceptive efficacy compared to other listed COCPs, but the PBAC said there is insufficient evidence to support claims that it has superior comparative safety.
• Nextstellis is suitable first line if a COCP is appropriate.
• Usual COCP precautions and contraindications apply.

Editor’s note: An earlier version of this article included safety and efficacy information from the manufacturer’s US website aimed at consumers; it has been updated to reflect the Australian product information.