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Frequently asked questions about NEXTSTELLIS®

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Questions about estetrol

  • What is estetrol (E4)?

    Estetrol is the first native estrogen approved for contraceptive use in the United States. Produced during pregnancy, estetrol is found at high levels in maternal–fetal circulation. For pharmaceutical use, estetrol can be produced from plants and offers a distinct pharmacologic profile from other contraceptive estrogens. Estetrol has selective actions on nuclear estrogen receptors and is the first estrogen to be described as a NEST: a Native Estrogen with Selective actions in Tissues.4-6,19,34 Find more information about how estetrol works.

  • What is a NEST estrogen, and how is it different? What benefits does it have for my patients?

    Estetrol is a Native Estrogen with Selective actions in Tissues (NEST).6 This describes several qualities that make estetrol unique. First, estetrol is an endogenous estrogen that occurs naturally during pregnancy.1,4 Second, it binds selectively to nuclear estrogen receptors while blocking estrogen receptors in the membrane. This makes estetrol pharmacologically distinct from other estrogens that bind both membrane and nuclear estrogen receptors throughout the body.9 Learn more about estetrol and its binding activity.

  • How is estetrol selective? What tissue types is it selective for?

    Tissues in the body respond differently to estrogen based on their dependence on nuclear or membrane receptor signaling.9,10

    • Other contraceptive estrogens bind widely to 2 main types of estrogen receptor—nuclear ERα and membrane ERα9,11,12
    • Estetrol binds selectively to nuclear estrogen receptors while blocking estrogen receptors in the membrane6

    Understanding the role of nuclear and membrane estrogen receptor signaling in different tissue types helps clarify the selective actions of estetrol.

    Tissue types predominantly dependent on membrane or nuclear ERα signaling



    Breast13 Stimulates growth



    Vascular System13 Prevents plaque accumulation



    Liver9,14 Impacts liver lipid metabolism



    Bone14,15 Maintains bone mineral density



    Uterus13 Supports tissue maintenance



    Vagina16 Supports tissue maintenance



  • Is estetrol as effective as other estrogens for controlling bleeding patterns?

    In clinical trials, NEXTSTELLIS demonstrated a highly predictable bleeding profile. Unscheduled bleeding with NEXTSTELLIS occurred in <2% of women in the trial, and the average duration of spotting or bleeding episodes was <1 day.7 Learn more about the bleeding patterns in Phase III studies of NEXTSTELLIS.

  • Is estetrol safer than other types of contraceptive estrogen?

    Estetrol offers a distinct pharmacologic profile compared with other types of estrogen because of its unique selective activity in tissues.4,6,19 Find more information about how estetrol works and the ways it impacts the body.

  • If estetrol is an endogenous estrogen, how is estetrol developed at scale for pharmaceutical use?

    Estetrol is an endogenous estrogen that occurs naturally during pregnancy. For pharmaceutical use, estetrol is produced from a plant source.1,5

Questions about NEXTSTELLIS

  • How is NEXTSTELLIS different from other oral contraceptives?

    NEXTSTELLIS pairs DRSP, a proven progestin, with the first newly approved contraceptive estrogen in 60 years—estetrol (E4).1,2,12 Estetrol binds selectively with nuclear estrogen receptor alpha (ERα) and antagonizes membrane ERα.9 Tissues in the body respond differently to estrogen based on their dependence on nuclear or membrane receptor signaling. This is what gives estetrol its unique tissue selectivity.9,10 Learn more about the mechanism of action of NEXTSTELLIS

  • Is NEXTSTELLIS a monophasic pill?

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

  • Why does NEXTSTELLIS contain drospirenone? Why not levonorgestrel?

    Estetrol—the estrogen component in NEXTSTELLIS—was studied (Phase II studies) in combination with drospirenone and levonorgestrel.1,22 Estetrol combined with either DRSP or LNG demonstrated adequate safety and efficacy.22 However, these and other Phase II studies also evaluated8,30,32,33:

    • Bleeding patterns
    • Hemostatic parameters
    • Endocrine parameters (including SHGB),
    • Lipid and carbohydrate metabolism parameters
    • Ovulation inhibition.

    Based on the results of these studies, drospirenone was selected as the optimal progestin to combine with estetrol.

  • How is dosing different with estetrol vs ethinyl estradiol? Why is the dose of estetrol in NEXTSTELLIS 14.2 mg?

    There are 3 key differences between estetrol and ethinyl estradiol that make a comparison in doses difficult:

    1. Estetrol is selective for nuclear ERα, whereas other contraceptive estrogens bind widely to both nuclear and membrane ERα6,9,11,12
      • Tissues in the body respond differently to estrogen based on their dependence on nuclear or membrane receptor signaling9,10
      • Estetrol activates nuclear ERα but antagonizes membrane ERα6
      • This is what gives estetrol its tissue selectivity6
      • Depending on the tissue, the differential effects of estetrol vs ethinyl estradiol will vary6,9,11
    2. Estetrol is much less potent and has lower binding affinity than ethinyl estradiol4,18,19
      • The estrogen receptor binding affinity of estetrol is approximately 5% compared with EE18,19
      • The downstream effects of E4 receptor binding are 1%-10% that of EE4,37
    3. Estetrol is minimally metabolized by the liver, whereas ethinyl estradiol is extensively metabolized by the liver4,38

    Because of these differences, the dose of E4 cannot be translated into an equivalent dose of EE that applies to all tissues.

    Ultimately, it is important to remember that estetrol is fundamentally different from synthetic contraceptive estrogens such as ethinyl estradiol. The lowest effective dose of estetrol + DRSP was established in Phase II dose-finding studies and validated in the Phase III studies that were the basis of its approval.1,7

  • What are the risks for VTEs with NEXTSTELLIS?

    Prescribing information for NEXTSTELLIS includes a boxed warning for women ≥35 years who are smokers.1 This is consistent with product labeling for combined hormonal contraceptives.

    In the Phase III clinical studies of NEXTSTELLIS, with a combined safety population of 3632, a VTE occurred in 1 patient in the EU/Russian trial, for an annual incidence rate of 3.66 per 10,000 women-years.1,36 The annual risk for VTE in women on any COC is estimated at 3 to 9 per 10,000 women. Longer-term studies will be needed to determine if there are differences in VTE risk with NEXTSTELLIS compared with any other COC.

  • Are the prescribing considerations different for NEXTSTELLIS than for other combined hormonal pills?

    NEXTSTELLIS shares the same prescribing considerations as other estrogen-containing birth control pills.1,39 For more information, please see the full Prescribing Information.

  • How should a patient start or transition to NEXTSTELLIS?

    Patients new to hormonal birth control can start NEXTSTELLIS on the first day of the menstrual cycle. Patients transitioning from other hormonal birth control methods can begin taking NEXTSTELLIS the day after stopping the previous method, or the next menstrual cycle.1

    Get comprehensive information about starting patients on NEXTSTELLIS. A downloadable patient brochure guide is also available for patients starting NEXTSTELLIS.

  • How can my patients save on NEXTSTELLIS?

    With the NEXTSTELLIS Savings Program, eligible patients may pay as little as $25* for a 1-month or 3-month prescription fill. Consider reducing your patients’ visits to the pharmacy and write a 3-month prescription.

    You can direct your patients to the Savings Page, where they will see instructions for downloading the NEXTSTELLIS Savings Card.

    *Depending on insurance coverage, eligible patients may pay as little as $25 for each of up to 12 one-month NEXTSTELLIS prescription fills OR each of up to 4 three-month NEXTSTELLIS prescription fills. Check with pharmacist for copay discount. Maximum savings limits apply; patient out-of-pocket expense will vary. Offer not valid for patients enrolled in Medicare, Medicaid, or other federal or state healthcare programs. Please see Program Terms, Conditions, and Eligibility Criteria here.

Program Terms, Conditions, and Eligibility Criteria

  1. This offer is valid only for eligible patients and is good for use only with a valid prescription for NEXTSTELLIS at the time the prescription is filled by the pharmacist and dispensed to the patient.
  2. Depending on your insurance coverage, most covered, insured, eligible patients will pay $25 for their prescription. Insured, eligible patients may incur out of pocket costs. Maximum reimbursement limits apply; patient out-of-pocket expenses may vary.
  3. This offer is not valid for use by patients enrolled in Medicare, Medicaid, or other federal or state programs (including any state pharmaceutical assistance programs), or private indemnity or HMO Insurance plans that reimburse the patient for the entire cost of the prescription drugs. Patients may not use this offer if they are Medicare-eligible and enrolled in an employer-sponsored health plan or prescription drug benefit program for retirees.
  4. This card is valid for up to 12 prescription fills.
  5. All prescriptions must be filled before the program expires on 12/31/23.
  6. Mayne Pharma reserves the right to rescind, revoke, or amend this offer without notice.
  7. Offer good only in the USA at participating retail pharmacies.
  8. Void if prohibited by law, taxed, or restricted.
  9. This card is not transferable. Selling, purchasing, trading, or counterfeiting this card is prohibited by law.
  10. This card expires on December 31, 2023.
  11. By redeeming this card, you acknowledge that you are a commercially insured, eligible patient and that you understand and agree to comply with the terms and conditions of this offer.

For questions about this program please call 347-442-7919.



See full prescribing information for complete boxed warning.

  • Females over 35 years old who smoke should not use NEXTSTELLIS

  • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.

IMPORTANT SAFETY INFORMATION FOR NEXTSTELLIS® (drospirenone and estetrol tablets 3 mg/14.2 mg)


These highlights do not include all the information needed to use NEXTSTELLIS safely and effectively. See full prescribing information for NEXTSTELLIS.

NEXTSTELLIS (drospirenone and estetrol tablets), for oral use
Initial U.S. Approval: 2021


NEXTSTELLIS is a combination of drospirenone, a progestin, and estetrol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy.

Limitations of Use

NEXTSTELLIS may be less effective in females with a BMI ≥30 kg/m2. In females with BMI ≥30 kg/m2, decreasing effectiveness may be associated with increasing BMI.


See full prescribing information for complete boxed warning.

  • Females over 35 years old who smoke should not use NEXTSTELLIS

  • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.


  • Take one tablet by mouth at the same time every day.
  • Take tablets in the order directed on the blister pack.


NEXTSTELLIS consists of 28 tablets in the following order:

  • 24 pink active tablets each containing drospirenone 3 mg and estetrol 14.2 mg
  • 4 white inert tablets


  • A high risk of arterial or venous thrombotic diseases
  • Current or history of a hormonally-sensitive malignancy (e.g., breast cancer)
  • Hepatic adenoma, hepatocellular carcinoma, acute hepatitis or decompensated cirrhosis
  • Co-administration with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir
  • Abnormal uterine bleeding that has an undiagnosed etiology
  • Renal impairment
  • Adrenal insufficiency


  • Thromboembolic Disorders and Other Vascular Problems: Stop NEXTSTELLIS if a thrombotic or thromboembolic event occurs. Start no earlier than 4 weeks after delivery. Consider all cardiovascular risk factors before initiating in any female, particularly in the presence of multiple risk factors.
  • Hyperkalemia: Check serum potassium concentration during the first NEXTSTELLIS treatment cycle in females on long-term treatment with medications that may increase serum potassium concentration.
  • Hypertension: Monitor blood pressure periodically and stop use if blood pressure rises significantly.
  • Migraine: Discontinue if new, recurrent, persistent, or severe migraines occur.
  • Hormonally-Sensitive Malignancy: Discontinue NEXTSTELLIS if a hormonally-sensitive malignancy is diagnosed.
  • Liver Disease: Withhold or permanently discontinue for persistent or significant elevation of liver enzymes.
  • Glucose Tolerance and Hypertriglyceridemia: Monitor glucose in females with prediabetes or diabetes. Consider an alternate contraceptive method for females with hypertriglyceridemia.
  • Gallbladder Disease and Cholestasis: Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder or cholestatic disease.
  • Bleeding Irregularities and Amenorrhea: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist.


Most common adverse reactions (≥2%): bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, weight increased, and libido decreased


  • CYP3A Inducers: May lead to contraceptive failure and/or increase breakthrough bleeding. Avoid concomitant use. If concomitant use is unavoidable, use an alternative or back-up contraceptive method during co-administration and up to 28 days after discontinuation of the CYP3A inducer.
  • See full Prescribing Information for additional clinically significant drug interactions.


  • Pregnancy: Discontinue if pregnancy occurs.
  • Lactation: Advise postpartum females that NEXTSTELLIS can decrease milk production.

To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or

See PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

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


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Ascenzi P, Bocedi A, Marino M. 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, Heegaard AM, Visser M, Holinka CF, Christiansen C. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric. 2008;11(suppl 1):2-14. 16. Benoit T, Valera MC, Fontaine C, 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. Shoham Z, Kopernik G. Tools for making correct decisions regarding hormone therapy. Part I: background and drugs. Fertil Steril. 2004;81(6):1447-1457. 18. Visser M, Foidart JM, Coelingh Bennink JT. In vitro effects of estetrol on receptor binding, drug targets, and human liver cell metabolism. Climacteric. 2008;11(suppl 1):64-68. 19. Blair R, Fang H, Branham WS, et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci. 2000;54:138-153. 20. Data on file. Clinical study report MIT‐Es0001‐C103. Mayne Pharma US. Greenville, NC. 21. Visser M, Holinka CF, Coelingh Bennink HJT. First human exposure to exogenous single-dose oral estetrol in early postmenopausal women. Climacteric. 2008;11(suppl 1):31-40. 22. Apter, D, Zimmerman Y, Beekman L, 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. 23. Regidor PA, Schindler A. Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone. Oncotarget. 2017;8(47):83334-83342. 24. Blode H, Kowal K, Roth K, Reif S. Pharmacokinetics of drospirenone and ethinyl estradiol in Caucasian and Japanese women. Eur J Contracept Reprod Health Care. 2012;17(4):284-297. 25. Levy T, Yairi Y, Bar-Hava I, et al. Pharmacokinetics of the progesterone-containing vaginal tablet and its use in assisted reproduction. Steroids. 2000;65(10-11):645-649. 26. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric. 2005;8(suppl 1):3-63. 27. Ortho Tri-Cyclen [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; October 2013. 28. Aygestin [package insert]. Pomona, NY: Duramed Pharmaceuticals Inc; July 2007. 29. Data on file. Clinical study report MIT‐Es0001‐C301. Mayne Pharma US. Greenville, NC. 30. Data on file. Clinical study report MIT‐Es0001‐C202. Mayne Pharma US. Greenville, NC. 31. Food and Drug Administration. Prescription and over-the-counter drug product list: additions/deletions for prescription drug product list. August 2015. Accessed May 21, 2021. 32. Data on file. Clinical study report ES-C01/PR3095. Mayne Pharma US. Greenville, NC. 33. Data on file. Clinical study report ES-C02. Mayne Pharma US. Greenville, NC. 34. Mayne Pharma and Mithra announce FDA approval of new oral contraceptive NEXTSTELLIS®. News release. Mayne Pharma. Accessed May 21, 2021. 35. Electronic Code of Federal Regulations. IND safety reporting. 21 CFR §312.32. Accessed May 21, 2021. 36. Data on file. NEXTSTELLIS New Drug Application, Module 2.5: Clinical Overview. Mayne Pharma US. Greenville, NC. 37. Holinka CF, Gurpide E. In vivo effects of estetrol on the immature rat uterus. Biology of Reproduction. 1979;20:242-246. 38. Coelingh Bennink HJT, Verhoeven C, Zimmerman Y. Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Climacteric. 2017;20(3):285-289. 39. Food and Drug Administration. Labeling for combined hormonal contraceptives: guidance for industry. Accessed May 11, 2021.