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Clinical data for NEXTSTELLIS® (drospirenone [DRSP]/estetrol [E4])

NEXTSTELLIS was studied in a population that included a range of ages and BMI.7,29 See how NEXTSTELLIS delivered across key endpoints in a large, multiphase clinical trial program.1,8,30

Overview of the NEXTSTELLIS clinical trial program

NEXTSTELLIS demonstrated efficacy and safety in a robust clinical trial program. The Phase III patient population included women 16 to 50 years of age and a high-BMI cohort (23% of patients had BMI 30-35 kg/m2). In Phase II studies, NEXTSTELLIS was compared head-to-head against 2 standard-of-care birth control pills—Yaz® (DRSP/EE) and Nordette® (LNG/EE).1,7,8,30,31

Click below to learn more about the trial design and endpoints in the:

NEXTSTELLIS Clinical Trials: Phase II included 681 patients in 4 trials. Phase III included 3632 in 2 trials

Phase II trial program

Dose-finding studies

In 2 Phase II dose-finding studies, 2 progestins (DRSP and LNG) were evaluated in combination with estetrol to determine32,33:

  • Minimum effective dose of estetrol
  • Most complementary progestin

Endpoints included32,33:

  • Ovulation inhibition
  • Bleeding patterns
  • Effect on liver parameters
  • Effect on sex hormone-binding globulin (SHBG)

Safety studies

In 2 Phase II safety studies, NEXTSTELLIS was studied head-to-head against 2 standard-of-care COCs8,30*:

  • Yaz® (20 mcg EE/3 mg DRSP)
  • Nordette®† (30 mcg EE/150 mcg LNG)

Endpoints included8,30:

  • Hemostasis parameters
  • Endocrine parameters, as well as SHBG
  • Lipid and carbohydrate metabolism parameters
  • Ovulation inhibition
*Both Phase II studies included Yaz® (EE/DRSP) as a comparator; only 1 (C201) included Nordette® (EE/LNG).
European trade name is Melleva®.31

Phase III trial program

Patient demographics reflect a real-world range in age, ethnicity, weight, and contraceptive history1,7,29

Phase III clinical trials included 3632 women from North America and the European Union aged 16 to 50 yearsPhase III clinical trials included 3632 women from North America and the European Union aged 16 to 50 years
Image Description

The 2 Phase III trials of NEXTSTELLIS studied 3632 women (ages 16-50 years). The efficacy population in the North American trial was 1524 (ages 16-35 years), and in the EU/Russian study, it was 1313 (ages 18-35 years). Women were studied over 12 months for 13 menstrual cycles, totaling 26,455 at-risk cycles.1,7,29

Patient demographics

CONTRACEPTIVE HISTORY7

  • Switching: 42%
  • Starting: 58%
    • Naive users: 17%

ETHNICITY7

  • Hispanic or Latino: 26%
  • Not Hispanic or Latino: 74%

WEIGHT7

  • 23% had BMI 30-35 kg/m2
    (mean BMI: 25.8 kg/m2)

RACE1

  • White: 70%
  • Black: 20%
  • Asian: 5%
  • American Indian or Alaskan Native: 1%
  • Native Hawaiian or Pacific Islander: 0.4%
  • Other: 4%

Phase III data: Results from a large and inclusive trial program

Key clinical endpoints from the North American Phase III trial

98%

Contraceptive efficacy

NEXTSTELLIS was 98% effective in preventing pregnancy (Pearl index: 2.65).1,7

BMI ≥30

Effective across body sizes

The high BMI subgroup (BMI 30-35 kg/m2) had a Pearl index of 2.94.1*

*NEXTSTELLIS may be less effective in women with BMI ≥30 kg/m2. In women with BMI ≥30 kg/m2, decreasing effectiveness may be associated with increasing BMI.1

In the Phase III study, bleeding patterns were similar to a natural, predictable menstrual cycle7

NEXTSTELLIS, with its 24/4 monophasic regimen, delivers a predictable bleeding pattern1,7

Scheduled
Bleeding

85%

On average, 85% of women experienced regular withdrawal bleeding (range: 82%-87% across cycles). Average duration was 4.5 days.7

Unscheduled
Bleeding

<2%

<2% of patients experienced unscheduled bleeding-only episodes after cycle 2.7

Average
Duration

<1 day

<1 day of any unscheduled spotting or bleeding on average per cycle after cycle 1.7

Treatment
Discontinuation

2.8%

2.8% of patients withdrew from treatment due to bleeding irregularities.1

Minimal unscheduled spotting or bleeding in the Phase III study even at cycle 1

The majority of patients who reported unscheduled spotting and/or bleeding experienced spotting only7

  • Spotting was defined as minimal bleeding that did not require the use of any sanitary protection (including pantyliners)7
  • 30% of patients had unscheduled spotting or bleeding at cycle 1, decreased to 22% at cycle 2, and remained <20% after cycle 47
  • The average duration of bleeding or spotting per cycle was <1 day after cycle 17

Per cycle, percentage of women reporting unscheduled spotting, mixed bleeding/spotting, or bleeding in the North American Phase III trial7

Over 12 cycle periods, women report incidents of bleeding, mixed bleeding/spotting, and spotting only
  • Over the entire study, bleeding-only episodes occurred in <2% of patients7
  • The bleeding profile was similar across patient subgroups (BMI ≥30 kg/m2, starters, and switchers)7

IMPORTANT SAFETY INFORMATION

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

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)

HIGHLIGHTS OF PRESCRIBING INFORMATION

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

INDICATIONS AND USAGE

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.

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

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.

DOSAGE AND ADMINISTRATION

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

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

  • 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

WARNINGS AND PRECAUTIONS

  • 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.

ADVERSE REACTIONS

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

DRUG INTERACTIONS

  • 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.

USE IN SPECIFIC POPULATIONS

  • 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 www.fda.gov/medwatch.

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.

References

1. NEXTSTELLIS [package insert]. Greenville, NC: Mayne Pharma; April 2021. 2. Szarewski A, Mansour D, Shulman LP. 50 years of “The Pill”: celebrating a golden anniversary. J Fam Plann Reprod Health Care. 2010;36(4):231-238. 3. Hall KS, Trussell J. Types of combined oral contraceptives used by U.S. women. Contraception. 2012;86(6):659-665. 4. Coelingh Bennink HJT, Holinka CF, Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric. 2008;11(suppl 1):47-58. 5. New data on NEXTSTELLIS presented at ISSWSH conference. News release. Mayne Pharma. Accessed May 21, 2021. https://www.maynepharma.com/investor-relations/company-announcements 6. Foidart JM, Gaspard U, Pequeux C, et al. Unique vascular benefits of estetrol, a native 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. Data on file. Clinical study report MIT‐Es0001‐C302. Mayne Pharma US. Greenville, NC. 8. Data on file. Clinical study report MIT‐Es0001‐C201. Mayne Pharma US. Greenville, NC. 9. Arnal JF, Lenfant F, Metivier R, et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev. 2017;97(3):1045-1087. 10. Moggs JG, Orphanides G. Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO Rep. 2001;2(9):775-781. 11. Stanczyk FZ, Archer DF, Bhavnani BR. Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013;87(6):706-727. 12. Food and Drug Administration. FDA label database. Accessed May 21, 2021. https://nctr-crs.fda.gov/fdalabel/ui/search 13. Abot A, Fontaine C, Buscato M, 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, 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. https://www.fda.gov/media/93516/download 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. https://www.maynepharma.com/media/2506/fda-approval-of-novel-oral-contraceptive-nextstellis.pdf 35. Electronic Code of Federal Regulations. IND safety reporting. 21 CFR §312.32. Accessed May 21, 2021. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 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. https://www.fda.gov/media/110050/download