Estetrol

CHCs prevent pregnancy primarily by suppressing ovulation.

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

• NEXTSTELLIS is contraindicated in females who are known to have or develop the following conditions: A history of, increased risk for, or current arterial or venous thrombotic/thromboembolic diseases.contraindicated

Take one tablet by mouth at the same time every day. ( 2.1 ) Take tablets in the order directed on the blister pack. ( 2.1 ) 2.1 Recommended Dosage and Administration Start NEXTSTELLIS using a Day 1 start. Take one tablet by mouth at the same time every day with or without food. 2.2 Additional Administration Information To achieve maximum contraceptive effectiveness, take one tablet every day at about the same time each day. The recommended dosage of NEXTSTELLIS is one tablet daily for 28 consecutive days: one pink active tablet daily during the first 24 days followed by one white inactive tablet daily during the 4 following days (see Table 1 ). Table 1 NEXTSTELLIS Administration Instructions Starting NEXTSTELLIS in females with no current use of hormonal contraception Important: In females with irregular menstrual cycles, pregnancy testing may be necessary prior to initiation of this product. Day 1 Start : Take the first pink active tablet on the first day of menses. Take subsequent pink active tablets once daily at the same time each day for a total of 24 days. Take one white inert tablet daily for 4 days and at the same time of day that active tablets were taken. Begin each subsequent 28-day pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) If not starting on the first day of menses, use a non-hormonal contraceptive (e.g. condoms and/or spermicide) as back-up until one active tablet has been taken daily for 7 days in a row.

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. ( 5.1 ) 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. ( 5.2 , 7.2 ) Hypertension : Monitor blood pressure periodically and stop use if blood pressure rises significantly. ( 5.3 ) Migraine : Discontinue if new, recurrent, persistent, or severe migraines occur. ( 5.4 ) Hormonally-Sensitive Malignancy: Discontinue NEXTSTELLIS if a hormonally-sensitive malignancy is diagnosed. ( 5.5 ) Liver Disease : Withhold or permanently discontinue for persistent or significant elevation of liver enzymes. ( 5.6 ) Glucose Tolerance and Hypertriglyceridemia : Monitor glucose in females with prediabetes or diabetes. Consider an alternate contraceptive method for females with hypertriglyceridemia. ( 5.8 ) Gallbladder Disease and Cholestasis : Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder or cholestatic disease. ( 5.9 ) Bleeding Irregularities and Amenorrhea : May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.11 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop NEXTSTELLIS if an arterial or venous thrombotic/thromboembolic event occurs.

The following clinically significant adverse reactions with the use of COCs are discussed elsewhere in labeling: Serious cardiovascular events including venous and arterial thromboembolism [see Boxed Warning and Warnings and Precautions (5.1) ] Hyperkalemia [see Warnings and Precautions (5.2) ] Liver disease [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥2%): bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, weight increased, and libido decreased ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data provided reflect the experience with the use of NEXTSTELLIS in two large prospective studies, one in Europe/Russia (C301) and one in North America (C302) (N = 3,632) of NEXTSTELLIS for the prevention of pregnancy in females 16-50 years of age. The mean duration of NEXTSTELLIS exposure was 317 and 257 days for the respective studies. The study population was 27 years of age on average, with a mean BMI of 25 kg/m 2 . The racial distribution was 83% White; 11% Black; 3% Asian; and 3% Other.

Pregnancy : Discontinue if pregnancy occurs. (8.1) Lactation : Advise postpartum females that NEXTSTELLIS can decrease milk production. ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue NEXTSTELLIS if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy [see Contraindications (4) ] . Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy. Reproductive toxicity studies performed with E4 alone have shown expected pharmacologic effects in animals, which are considered consistent with estrogen exposure. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively. 8.2 Lactation Risk Summary Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. When possible, advise the nursing woman to use other methods of contraception until she discontinues breast-feeding [see also Dosage and Administration (2.1) ] .

Metabolism

Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic properties of E4 and DRSP following administration of NEXTSTELLIS are provided in TABLE 8. Table 8.

Overdosage of CHCs may cause nausea, vomiting, and severe headaches. Individual reports of thromboembolic complications and vaginal bleeding have occurred from overdosage. Pediatric patients with unintended CHC ingestion have reported nausea and vomiting and some developed irritability and drowsiness; rare reports described vaginal bleeding. Overdosage Management Recommendations Consider short-term prophylactic anticoagulation therapy for patients with high risk of VTE. Monitor serum potassium and sodium levels, and for evidence of metabolic acidosis.

• Apr 15, 2021NDANDA214154Mayne Pharma

1. 1Intermenstrual Bleeding2310%
2. 2Heavy Menstrual Bleeding188.0%
3. 3Headache135.8%
4. 4Dizziness114.9%
5. 5Mood Swings104.4%
6. 6Drug Ineffective94.0%
7. 7Migraine94.0%
8. 8Nausea94.0%
9. 9Suicidal Ideation94.0%
10. 10Menstruation Irregular83.6%
11. 11Pulmonary Embolism83.6%
12. 12Weight Increased83.6%
13. 13Breast Tenderness73.1%
14. 14Malaise73.1%
15. 15Acne62.7%

Recent PubMed references pinned to Estetrol as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

• Estetrol (E4) for the treatment of moderate to severe vasomotor symptoms in postmenopausal women - Efficacy and safety results from the phase 3 E4COMFORT I multicenter, placebo-controlled study.
  Maturitas · 2026 · Simoncini T, Bouchard C, Cloes M, et al.
  PMID 42068869DOI 10.1016/j.maturitas.2026.108965
• Continuous estetrol/drospirenone regimen for the treatment of endometriosis-related pain: preliminary results.
  Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology · 2026 · Dell'Aquila M, Della Corte L, Kafetzis D, et al.
  PMID 42018156DOI 10.1080/09513590.2026.2662694
• Estetrol-based combined oral contraceptives: A systematic review of clinical outcomes.
  Acta obstetricia et gynecologica Scandinavica · 2026 · Råberg M, Vad IR, Axelsdóttir KH, et al.
  PMID 41988925DOI 10.1111/aogs.70203
• Estetrol Enhances Mitochondrial Bioenergetics and Neurite Outgrowth in Cellular Models of Alzheimer's Disease.
  Cells · 2026 · Grimm A, Riou A, Gaillard C, et al.
  PMID 41827885DOI 10.3390/cells15050452
• A concept for a new approach to combined oral contraception from adolescence to perimenopause: Continuous use of the oral GnRH antagonist Relugolix and the fetal estrogen Estetrol.
  Acta obstetricia et gynecologica Scandinavica · 2026 · Coelingh Bennink HJT, Afors K, Bahamondes L, et al.
  PMID 41793206DOI 10.1111/aogs.70182
• Delayed start of estetrol drospirenone versus ethinyl estradiol gestodene for ovulation inhibition in a noninferiority randomized controlled trial.
  Scientific reports · 2025 · Ittipuripat S, Phutrakool P, Uaamnuichai S, et al.
  PMID 41388035DOI 10.1038/s41598-025-27467-y
• Estetrol for the treatment of moderate to severe vasomotor symptoms in postmenopausal women: The design of the E4COMFORT I and II trials.
  Maturitas · 2026 · Panay N, Simoncini T, Taziaux M, et al.
  PMID 41289787DOI 10.1016/j.maturitas.2025.108781
• Estetrol prevents estradiol-induced precancerous cell proliferation in mice.
  Biochemical and biophysical research communications · 2025 · Itou J
  PMID 41187432DOI 10.1016/j.bbrc.2025.152908

The 10 most recently updated of 34 ClinicalTrials.gov registrations naming Estetrol as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Arterial Vascular Effects of Estetrol-drospirenone Combined Oral Contraceptive Pill
  Not yet recruiting · Phase 3 · Interventional · 98 enrolled · Dr. Hang Wun Raymond Li
  NCT07536763updated 2026-04-27
• Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort II)
  Completed · Phase 3 · Interventional · 1,015 enrolled · Estetra
  NCT04090957updated 2025-12-26
• Estetrol for the Treatment of Female Sexual Arousal Disorder in Postmenopausal Women
  Completed · Phase 2 · Interventional · 82 enrolled · Estetra
  NCT06308614updated 2025-09-03
• International Active Surveillance Study: Safety of Estrogen Estetrol (E4) Contraceptive Study (INAS-SEECS)
  Recruiting · Observational · 68,100 enrolled · Center for Epidemiology and Health Research, Germany
  NCT06186271updated 2025-08-20
• International Active Surveillance Study: Native Estrogen Estetrol (E4) Safety Study
  Recruiting · Observational · 101,000 enrolled · Center for Epidemiology and Health Research, Germany
  NCT06028555updated 2025-08-17
• Prospective Evaluation on the Role Exerted by Hormonal Contraceptives on 24-h Blood Pressure. A Prospective Observational Study
  Recruiting · Observational · 96 enrolled · Ospedale Policlinico San Martino
  NCT07061093updated 2025-07-11
• Single and Multiple Intravenous Administrations of Estetrol (E4) in Healthy Adult Volunteers
  Terminated · Phase 1 · Interventional · 8 enrolled · NEURALIS s.a.
  NCT05460065updated 2025-07-04
• "Quick-starting" of a New Combined Hormonal Contraceptive Pills, 15 mg Estetrol/3 mg Drospirenone VS 20 mcg Ethinylestradiol/75 mcg Gestodene Focusing on Ovulation Inhibition
  Completed · Interventional · 36 enrolled · Chulalongkorn University
  NCT06396221updated 2025-05-20
• Estetrol/Drospirenone to Reduce the Average Size of Endometriomas
  Recruiting · Phase 4 · Interventional · 21 enrolled · Andrew Zakhari
  NCT05837624updated 2025-04-06
• Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I)
  Completed · Phase 3 · Interventional · 1,570 enrolled · Estetra
  NCT04209543updated 2025-01-29

Frequently asked questions

How does Estetrol work?

CHCs prevent pregnancy primarily by suppressing ovulation.

What is Estetrol used for?

According to FDA labeling, Estetrol carries indications including: NEXTSTELLIS is indicated for use by females of reproductive potential to prevent pregnancy. NEXTSTELLIS is a combination of drospirenone, a progestin, and estetrol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Estetrol?

Estetrol is classified as Natural and semisynthetic estrogens, plain, Estrogen, Estrogen Receptor Agonists, Ovulation Alteration.

What are the contraindications for Estetrol?

Estetrol labeling lists contraindications including: NEXTSTELLIS is contraindicated in females who are known to have or develop the following conditions: A history of, increased risk for, or current arterial or venous thrombotic/thromboembolic diseases.. Always consult the full prescribing information and a clinician.