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Introducing E4 : the estrogen that makes NEXTSTELLIS unique6

Native

Produced during pregnancy1,31-35

  • E4 is produced naturally by the foetus during pregnancy
  • The E4 in NEXTSTELLIS made from a plant source, to match the body’s naturally occurring E4
Selective

A low impact* estrogen2

  • *Based on its selectivity, potency, pharmacokinetics, mechanism of action and impact on the liver and breast.ɤ 
     

    ɤ Tissue proliferation, as demonstrated in murine mammary gland in-vitro and in-vivo studies 32

Understanding the selective actions of estetrol

Estetrol is selective for tissues that depend predominantly on nuclear estrogen receptors6

Tissues in the body respond differently to estrogen based on their dependence on nuclear or membrane receptor signaling.6

Other estrogens in contraception activate both the nuclear and membrane alpha receptors.2,13

Nuclear icon

Tissue selectivity

E4 activates nuclear ERα but antagonizes membrane ERα. This gives E4 selective effects in different tissue types.6

Tissue types predominantly dependent on membrane or nuclear ERα signaling9

NUCLEAR DEPENDENT

Nucleaus icon

MEMBRANE DEPENDENT

Membrane icon

Breast13 Stimulates growth

NO

YES

Vascular System13 Prevents plaque accumulation

YES

NO

Liver9,14 Impacts liver lipid metabolism

YES

YES

Bone14,15 Maintains bone mineral density

YES

YES

Uterus13 Supports tissue maintenance

YES

NO

Vagina16 Supports tissue maintenance

YES

NO

Why E4?

Most combined contraceptives use ethinylestradiol (EE)—a synthetic, modified form of estradiol (E2).11,17

What makes E4 different? 2,4
  • E4 is a low impact* estrogen1,2
  • E4 has selective action in tissues - minimal impact on the liver and breastɤ compared to other estrogens 2,13
  • No interconversion to other estrogens or recirculation of active metabolites1,2,4
  • Less potent than EE or E24,13
  • Minimal interaction with CYP4501,18

*Based on its selectivity, potency, pharmacokinetics, mechanism of action and impact on the liver. 
 ɤTissue proliferation, as demonstrated in murine mammary gland in-vitro and in-vivo studies.32

Chemical structures of estetrol and ethinyl estradiol
Image Description

Chemical structures of estetrol, a 4-ring estrogen structure with 4 hydroxyl groups, and ethinyl estradiol, a 4-ring structure with an ethinyl group at the 17-position and 2 hydroxyl groups.

Why Drospirenone?

Drospirenone (DRSP) was selected as the progestin component of NEXTSTELLIS based on results of Phase II studies evaluating E4/DRSP compared with E4/LNG.8,21,26,27,30

What makes DRSP different?

  • Similar activity in the body as natural progesterone1
  • Anti-mineralocorticoid properties22
  • Anti-androgenic properties22
  • Long half-life (~30 hours)1,36,37

Progestin Comparison1,22 

progestinsArtboard 1

 

PBS Information: THIS PRODUCT IS NOT LISTED ON THE PBS.

 

IMPORTANT SAFETY INFORMATION FOR NEXTSTELLIS® (estetrol/drospirenone tablets) 

As NEXTSTELLIS contains estetrol, a new molecular entity, it qualifies for the TGA’s Black Triangle Scheme. ▼ This medicinal product is subject to additional monitoring in Australia. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse events at www.tga.gov.au/reporting-problems

BMI=body mass index; COC=combined oral contraceptive; EU=European Union; HDL=high-density lipoprotein; LDL=low-density lipoprotein; LNG=levonorgestrel. EE=ethinylestradiol; DRSP=drospirenone

References

1. NEXTSTELLIS Product Information. 2. Gérard C, et al. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert Review of Clinical Pharmacology 2022; 15:2, 121-137. 3. Drovelis EMEA authorisation. European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/EPAR/drovelis#authorisation-details-section [accessed on 18 Jul 2022]. 4. Coelingh Bennink HJT, et al. Estetrol review: profile and potential clinical applications. Climacteric. 2008;11(suppl 1):47-58. 5. Lydisilka EMEA authorisation. European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/EPAR/lydisilka#authorisation-details-section [accessed on 18 Jul 2022]. 6. Foidart JM, et al. Unique vascular benefits of estetrol, a natural fetal estrogen with specific actions in tissues (NEST). In: Brinton RD, Genazzani AR, Simoncini T, Stevenson JC, eds. Sex Steroids’ Effects on Brain, Heart and Vessels. Volume 6: Frontiers in Gynecological Endocrinology. New York, NY: Springer International Publishing; 2019:169‐195. 7. Creinin M, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021; 104: 222–228 8. Douxfils J, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6): 396–402. 9. Arnal JF, et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev. 2017;97(3):1045-1087. 10. Nextstellis Approval FDA. U.S. Food & Drug Administration (FDA). https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=214154 [accessed on 18 Jul 2022]. 11. Stanczyk FZ, et al. Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013;87(6):706-727. 12. Jensen JT, et al. Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials. Contraception. 2022; DOI: https://doi.org/10.1016/j.contraception.2022.07.009. Epub ahead of print. PMID: 35921870. 13. Abot A, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6(10):1328-1346. 14. Ascenzi P, et al. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Aspects Med. 2006;27(4):299-402. 15. Coelingh Bennink HJT, et al. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric. 2008;11(suppl 1):2-14. 16. Benoit T, et al. Estetrol, a fetal selective estrogen receptor modulator, acts on the vagina of mice through nuclear estrogen receptor α activation. Am J Pathol. 2017;187(11):2499-2507. 17. Fruzzetti F, et al. Estetrol: A New Choice for Contraception. J. Clin. Med. 2021, 10, 5625. https://doi.org/10.3390/jcm10235625. 18. Visser M, et al. In vitro effects of estetrol on receptor binding, drug targets, and human liver cell metabolism. Climacteric. 2008;11(suppl 1):64-68. 19. Nextstellis Approval Health Canada. Health Canada, Government of Canada. 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=100241 [accessed on 18 Jul 2022]. 20. Kestemont P, et al. 2020. Poster 0175 presented at the Society of Family Planning Virtual Annual Meeting October 9 10, 2020. 21. Apter D, et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception. 2016;94(4):366-373. 22. Regidor PA, et al. Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone. Oncotarget. 2017;8(47):83334-83342. 23. Data on file – Mithra Pharmaceuticals from MIT-ES0001-C301; MIT-ES0001-C302. 24. Kaunitz AM, et al. Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women. Contraception. 2022 Jul 31:S0010-7824(22)00218-9. doi: 10.1016/j.contraception.2022.07.010. Epub ahead of print. PMID: 35921872. 25. Gemzell-Danielsson K, et al. Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG. 2022; 129: 63-71. 26. Klipping C, et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021;103(4): 213–221. 27. Mawet M, et al. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur. J. Contracept. Reprod. Health Care 2015, 20, 463–475. 28. NEXTSTELLIS ARTG ID 341876 available at http://www.ebs.tga.gov.au [accessed on 21 June 2021]. 29. Chen M, et al. Submitted Manuscript 2022. 30. Duijkers I, et al. Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function. Contraception 103 (2021) 386–393. 31. Holinka CF & Gurpide E. In vivo effects of estetrol on the immature rat uterus. Biology of Reproduction. 1979;20:242-246. 32.  Gérard C, et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. Journal of Endocrinology 2015; 224, 85–95. 33. Lee A & Syed YY. Estetrol/Drospirenone: A Review in Oral Contraception. Drugs. 2022 Jul 4. doi: 10.1007/s40265-022-01738-8. Epub ahead of print. PMID: 35781795. 34. Holinka CF, et al. Estetrol: A unique steroid in human pregnancy. J Steroid Biochem Mol Biol. 2008; 110(1–2): 138–143. 35. Warmerdam EG, et al. A new route of synthesis of estetrol. Climacteric. 2008; 11(suppl 1): 59–63. 36. YAZ Product Information. 37. SLINDA Product Information.

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