No Proven Advantage for the New Combined Birth Control Pill Drospirenone and Estetrol (NEXTSTELLIS)

One of the most common methods of contraception (birth control) is combined oral contraceptive pills. These medications contain two types of hormones: a progestin (which primarily inhibits ovulation) and an estrogen (which balances the effect progestin has on the uterus to provide an acceptable bleeding pattern and contributes to the contraceptive activity).[1]

In May 2021, the Food and Drug Administration (FDA) approved a new 28-day, fixed-dose, combined oral contraceptive called NEXTSTELLIS, which includes an old form of progestin (drospirenone) and a new form of estrogen (estetrol).[2],[3]

The makers of Nextstellis claimed that it represents a “new era” in contraception and predicted that it will become the preferred brand-name contraceptive on the market.[4] However, the limited clinical-trial evidence used to support the approval of this drug does not show that it offers any proven advantage over older, well-studied, combined oral contraceptives. In contrast, the drospirenone component of Nextstellis is well-known to increase the risk of blood clots, and this risk has not been adequately evaluated in users of Nextstellis.[5] Therefore, Public Citizen’s Health Research Group has designated Nextstellis as a Do Not Use medication, consistent with our designation of other drospirenone-containing combined oral contraceptives.[6]

Limited evidence on the effectiveness of Nextstellis

The makers of Nextstellis claimed that its estrogen component (estetrol) — which is a new molecule that had not been approved in the United States before[7] — has a selective action on the tissues involved in contraception.[8],[9] However, this claim is based on in vitro (laboratory) evidence rather than large clinical trials that compared its use with that of ethinyl estradiol — which is the standard estrogen component in older hormonal contraceptives — in female patients.

Unfortunately, the FDA does not require new contraceptives to be compared directly (head-to-head) with previously approved ones and just approves these medications based on their individual benefit–risk profiles.[10] In fact, the agency indicates that its standard for approving these medications is that their benefits only need to outweigh the risks associated with unintended pregnancy. Therefore, the agency approved Nextstellis based on an open-label, single-arm North American trial that included 1,864 women — most of whom were between the ages of 16 and 35 — who took at least one dose of Nextstellis over the course of one year. The FDA also considered supportive evidence from a similarly designed one-year European trial that enrolled 1,553 women. Based on the North American study, the number of unintended pregnancies (which is called the Pearl index) was about two per 100 women users.[11] However, only 47% of the subjects in this trial completed it.[12] The FDA concluded that the Pearl index for Nextstellis is equivalent to that associated with clinical trials involving other combined hormonal contraceptives. However, such indirect comparisons are problematic.

Risks of drospirenone

Nextstellis contains a fourth-generation progestin called drospirenone. Drospirenone is similar to spironolactone (ALDACTONE) — a potassium-sparing diuretic (water pill) that is used to treat hypertension — and can cause the body to retain potassium. Other combined contraceptive pills that have been on the U.S. market since 2001 that also contain drospirenone — in addition to ethinyl estradiol — include LORYNA, MELAMISA, NIKKI, YASMIN, YAZ and many others. These older drospirenone-containing pills have been linked to an increased risk of venous thromboembolism (a condition in which blood clots form in the veins). For example, the labeling of Yasmin warns that “studies that compared the risk of [venous thromboembolism] reported that the risk ranged from no increase to a three-fold increase.”[13]

In fact, in their evaluation of Nextstellis, FDA scientists indicated that the U.S. experience about the risk of venous thromboembolism as found in observational epidemiologic studies “stretches over the past 50 years.” They also acknowledged these studies show that combined oral contraceptives that contain drospirenone (in addition to ethinyl estradiol) have been associated with a potential increased risk of venous thromboembolism, compared with second-generation combined oral contraceptives, which contain other progestins (levonorgestrel and norgestrel).[14]

Moreover, the very limited premarketing evidence for Nextstellis showed that two users of this drug developed blood clots.[15] Unfortunately, there is no epidemiological evidence that can be used to determine the risk of thromboembolism in the general population of females who are expected to use this new pill. Nonetheless, the FDA determined that the safety profile for Nextstellis was acceptable and is similar to that of other combined oral drospirenone-containing contraceptives.

Additionally, the agency required Mayne Pharma, the primary maker of Nextstellis, to conduct either a postmarketing study using electronic health records or a primary data collection observational cohort study to determine the risks of fatal and nonfatal venous thromboembolism and arterial thromboembolism in users of this drug.[16] The FDA also required the drug maker to compare these users with users of older drospirenone-containing and non-drospirenone-containing combined oral contraceptives. However, the submission of this evidence and the final report are not expected to be available until June 2027. Similarly, the European Medicines Agency also is requiring a postmarketing study to assess the risk of blood clots from use of Nextstellis.[17]

Other possible serious risks associated with the drospirenone component of Nextstellis include hypertension (high blood pressure) and hyperkalemia (elevated levels of potassium in the blood).[18] The latter risk can lead to heart palpitations (feeling that one’s heart is racing or fluttering), irregular heartbeat, shortness of breath, severe chest pain, nausea, vomiting, muscle weakness and numbness the extremities. In the two trials involving Nextstellis, seven subjects developed hyperkalemia, and one subject discontinued the drug due to this adverse effect.

What You Can Do

If you are considering using combined oral contraceptive pills, you should avoid Nextstellis. Likewise, you should avoid the use of other combined oral contraceptives that contain drospirenone or the third-generation progestin called desogestrel. Notably, we petitioned the FDA, unsuccessfully, to ban desogestrel-containing oral contraceptives in 2007 because they double the risk of blood clots without offering any proven therapeutic advantage.[19]

Instead, you may consider combined contraceptive pills that contain second-generation progestins (levonorgestrel or norethisterone) in addition to low-dose ethinyl estradiol.[20] Although the use of any type of combined oral contraceptive carries an increased risk of blood clots, this risk is lower with these pills.

Do not stop taking your contraceptive pills suddenly; if you need to switch to a different contraceptive pill, follow your doctor’s instructions to minimize the risk of pill failure.

If you are over the age of 35 or use nicotine-containing products, you should not use contraceptive pills, because these factors increase your risk of serious cardiovascular events.[21] Also, you should not use any oral contraceptives if you take any hepatitis C drug that contains ombitasvir, paritaprevir and ritonavir (VIEKIRA PAK, VIEKIRA XR) or if you have any of the following conditions:

• a history of blood clots, angina pectoris (chest pain), heart attack or stroke
• jaundice (yellowing of your skin or the whites of the eyes) or liver tumor
• known or suspected breast cancer or cancer of the lining of the uterus
• unexplained vaginal bleeding

Users of any form of oral contraceptive should know that they do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

Report all serious adverse events associated with the use of Nextstellis or other medications to the FDA’s MedWatch adverse-event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] European Medicines Agency. Assessment report for drospirenone/estetrol (DROVELIS). March 25, 2021. https://www.ema.europa.eu/en/documents/assessment-report/drovelis-epar-public-assessment-report_en.pdf. Accessed May 8, 2023.

[2] Food and Drug Administration. Approval letter for drospirenone and estetrol (NEXTSTELLIS). April 15, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214154Orig1s000ltr.pdf. Accessed May 8, 2023.

[3] Mayne Pharma. Label: drospirenone and estetrol (NEXTSTELLIS). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214154s002lbl.pdf. Accessed May 8, 2023.

[4] Mayne Pharma and Mithra Pharmaceuticals. Joint press release. ESTELLE contraceptive now available in the United States. June 21, 2021. https://www.mithra.com/wp-content/uploads/2021/06/2021-06-21-NEXTSTELLIS-launch-announcement-EN.pdf. Accessed May 8, 2023.

[5] Food and Drug Administration. FDA drug safety communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone. April 10, 2012. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-information-about-risk-blood-clots-women-taking-birth-control. Accessed May 8, 2023.

[6] Oral contraceptives containing drospirenone - increased risk of blood clots. Worst Pills, Best Pills News. May 2011. https://www.worstpills.org/newsletters/view/743. Accessed May 8, 2023.

[7] Food and Drug Administration. Multi-disciplinary review and evaluation of drospirenone and estetrol (NEXTSTELLIS). NDA 214154. April 15, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214154Orig1s000MultidisciplineR.pdf. Accessed May 8, 2023.

[8] Mayne Pharma and Mithra Pharmaceuticals. Joint press release. ESTELLE contraceptive now available in the United States. June 21, 2021. https://www.mithra.com/wp-content/uploads/2021/06/2021-06-21-NEXTSTELLIS-launch-announcement-EN.pdf. Accessed May 8, 2023.

[9] Food and Drug Administration. Multi-disciplinary review and evaluation of drospirenone and estetrol (NEXTSTELLIS). NDA 214154. April 15, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214154Orig1s000MultidisciplineR.pdf. Accessed May 8, 2023.

[10] Ibid.

[11] Mayne Pharma. Label: drospirenone and estetrol (NEXTSTELLIS). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214154s002lbl.pdf. Accessed May 8, 2023.

[12] Food and Drug Administration. Multi-disciplinary review and evaluation of drospirenone and estetrol (NEXTSTELLIS). NDA 214154. April 15, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214154Orig1s000MultidisciplineR.pdf. Accessed May 8, 2023.

[13] Bayer HealthCare Pharmaceuticals Inc. Label: drospirenone and ethinyl estradiol (YASMIN). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021098s030lbl.pdf. Accessed May 8, 2023.

[14] Food and Drug Administration. Multi-disciplinary review and evaluation of drospirenone and estetrol (NEXTSTELLIS). NDA 214154. April 15, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214154Orig1s000MultidisciplineR.pdf. Accessed May 8, 2023.

[15] Ibid.

[16] Food and Drug Administration. Approval letter for drospirenone and estetrol (NEXTSTELLIS). April 15, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214154Orig1s000ltr.pdf. Accessed May 8, 2023.

[17] European Medicines agency. Section VI: Summary of risk management plan for DROVELIS. 2021. https://www.ema.europa.eu/en/documents/rmp-summary/drovelis-epar-risk-management-plan-summary_en.pdf. Accessed May 8, 2023.

[18] Mayne Pharma. Label: drospirenone and estetrol (NEXTSTELLIS). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214154s002lbl.pdf. Accessed May 8, 2023.

[19] Public Citizen. Petition to the FDA to ban third generation oral contraceptives containing desogestrel due to increased risk of venous thrombosis. February 6, 2007. https://www.citizen.org/wp-content/uploads/migration/1799.pdf. Accessed May 8, 2023.

[20] Oral contraceptives containing drospirenone - increased risk of blood clots. Worst Pills, Best Pills News. May 2011. https://www.worstpills.org/newsletters/view/743. Accessed May 8, 2023.

[21] Glenmark Pharmaceuticals. Label: norethindrone and ethinyl Estradiol (BRIELLYN). May 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=c0e2c5b4-70ac-4b41-aa71-00e506dbb72f&type=display. Accessed May 8, 2023.