A new combined oral contraceptive was approved by the FDA (Nextstellis®) in April 2021.¹ Nextstellis contains estetrol, an estrogen that can be manufactured from plants and that was originally derived naturally during pregnancy from the fetus liver, and drospirenone, a progestin found in other currently available contraceptives. Drospirenone has antiandrogenic and anti-mineralocorticoid activity.² Estetrol differs from ethinyl estradiol in that has selective antagonistic and agonistic estrogen receptor activity, while ethinyl estradiol has exclusively agonist activity. With perfect use, Nextstellis is effective as a contraceptive for females between the ages of sixteen and fifty. These results are supported by data from two Phase III trials which obtained the drug’s safety and success over an extensive trial program. This research consisted of 3632 women between the ages of sixteen and fifty with 23% of patients having a BMI of 30-35 kg/m². In the North American Phase III trial alone, 1524 women between the ages of sixteen to thirty-five years were tested over 12 months for 13 menstrual cycles and the clinical endpoint was that Nextstellis is 98% effective in preventing pregnancy when taken correctly.¹

The current recommended dosing is one tablet by mouth daily in the order provided by the blister pack for 28 days. The blister pack contains twenty-four active ingredient pills followed by four inert pills. The first active tablet should be taken on the first day of the menstrual cycle daily at the same time every day. If Nextstellis is not taken on the first day of menses an additional non-hormonal contraceptive method should be used for the first seven days.¹ Nextstellis can be taken with or without food.²

Contraindications of Nextstellis

Patients should avoid use of Nextstellis prior to menarche or if they are postmenopausal.² Nextstellis has a black box warning for women over the age of 35 who smoke.  Like other estrogen-containing contraceptives, this drug is contraindicated in women with a high risk, or current diagnosis, of thrombotic diseases. Nextstellis is also contraindicated in patients who have a history, or current diagnosis, of hormonal cancers such as breast cancer, renal impairment, adrenal insufficiency, and certain liver diseases: hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or decompensated cirrhosis. Additionally, this drug cannot be administered in conjunction with hepatitis C drugs that contain ombitasvir/ paritaprevir/ ritonavir. Drug interactions for Nextstellis include CYP3A inducers and the patient should use an alternative contraception method for up to 28 days after the last dose of a CYP3A inducer. ² Lastly, Nextstellis should not be used when there is undiagnosed and abnormal vaginal bleeding.¹  

Other warnings and precautions include gallbladder disease, cholestasis, and liver disease in which case the drug should be discontinued. If hypertension or hyperkalemia occurs, monitor periodically and discontinue if levels persist outside of normal parameters. Additionally, Nextstellis should be discontinued if migraines are new, persistent, and severe to the patient.¹ Females with prediabetes and diabetes should monitor their blood glucose levels, and females with hypertriglyceridemia should consider a different birth control as this may increase the risk of pancreatitis.²

Limitations of Use

The limitations of Nextstellis is that it could be less effective in obese patients with a body mass index equal to or greater than 30 kg/ m². Within the studied population, 23% accounted for women with a BMI between 30- 35 kg/ m ². The Pearl Index for women with a BMI <30 was 2.57, and it was 2.94 for women with a BMI between >30 and 35. ¹ The Pearl Index is equal to the number of women that get pregnant out of 100 women per year. As the BMI increased in the women participating in the study, the Pearl Index also increased. The lower the Pearl Index, the more effective the use of contraceptives. ²

Adverse Reactions

The most common adverse reactions (>2%) were bleeding irregularities, dysmenorrhea, headaches, mood disturbance, increase weight, acne, decrease libido and breast symptoms.¹ Mood disturbances were classified as irritability, anxiety, insomnia, panic disorder, restlessness and suicidal ideation. Breast symptoms included breast enlargement and sensitivity.²   These side effects are common in all combination oral contraceptives. Prescribers and dispensers should educate their patients that these symptoms are likely to occur, and most side effects will begin to resolve after three to five months of therapy when the body has adjusted to the hormonal changes. ³

Unique Features

While there are several other combination oral contraceptives on the market, Nextstellis has unique features that distinguishes it from other oral contraceptives. First, the estrogen component is estetrol, whereas most other contraceptives contain ethinyl estradiol. According to Grandi and colleagues  the selective actions of estetrol can lead to fewer side effect because the half-life of estetrol is 20- 28 hours, whereas other estrogens like estriol have a half-life of 10- 20 minutes and estradiol has a half-life of 1-2 hours. Estetrol is also minimally converted to estriol and estradiol. The longer half-life and the minimal metabolism to other estrogen forms, allows this drug to be  available for a longer period of time to bind at the receptor sites.⁴ Specifically, Nextstellis selectively binds to the nuclear estrogen receptor and it is described to be a native estrogen with selective action in tissues. ¹ In pharmacologic studies, it was proven that estetrol acts as an estrogen in bones, uterus, and vagina. ⁵ 

Clinical Trials

In addition to providing a contraceptive option for women who are unable to tolerate ethinyl estradiol, Nextstellis has demonstrated overall low rates of common side effects found in oral contraceptives such as acne, libido changes and breast pain in two Phase III studies (North American trial and the EU/Russian study).¹ Animal data demonstrated that estetrol had a 100 times weaker effect on breast tissue proliferation in vitro human cells along with in vivo mouse mammary glands than estradiol.³ Although early animal studies have shown that estetrol has less of a damaging effect on breast tissue and may have a lower impact on the risk of breast cancer for humans, there needs to be more studies to solidify this data. ⁴

Interventional studies on Nextstellis have demonstrated less outcomes of deterrent side effects common to hormonal contraceptives such as breakthrough bleeding. Less than 2% of patients in the Phase III study experienced unscheduled bleeding episodes after cycle 2.¹ In the FIESTA study it was shown that estetrol combined with drospirenone (E4/DRSP) compared with  quadriphasic estradiol valerate and dienogest (E2 V/DNG) had different frequencies for unscheduled bleeding. Breakthrough bleeding was present in 33.8% of the E4/DRSP group group versus 47.8% of the E2 V/DNG group. There was an additional study that showed overall satisfaction of being on E4/DRSP was higher than E2 V/DNG when patients took a self-reported Subject Satisfaction and Health-Related Questionare.⁴

Environmental Impact           

Estetrol is beneficial because it is less likely to contribute to water pollution and harm to the environment than estradiol (E2) or ethinyl estradiol (EE2).⁶ Nextstellis is metabolized in a unique way where less of the drug ends up being in the urine and therefore less of it ends up in our water system. This drug is made through a plant-based procedure, unlike other estrogens. Estrogens like ethinyl estradiol are not metabolized well, leading to build up in the body. Ethinyl estradiol is excreted in the urine and ends up in bodies of water, where it can lead to damage to marine life’s growth and ability to reproduce, whereas estetrol’s ability to be decomposed more quickly can be more environmentally friendly. According to Mirtha Women’s Health Pharmaceutics, levels as low as 1ng/L of E2 and EE2 in fish environments can lead to adverse effects and are far more potent than having 32,000 ng/L of estetrol. Adverse side effects, including reduced testicular growth, development of ova-testes in males, reduced egg production, delayed maturation, and the population ratio skewed towards females^. are severely affecting the fishes reproductive health⁶.

In conclusion, Nextstellis is a recent FDA-approved oral contraceptive that offers patients another alternative for birth control. Nextstellis’ active estrogen is estetrol which is unique compared to other combination oral contraceptives. While not stated in the current package insert, data are emerging that support fewer breast tissue effects and breakthrough bleeding than older oral contraceptives. Overall, Nextstellis is a safe and effective contraceptive option. 

About the Authors

Athina Herrera Ng, PharmD Candidate 2023, is currently in her third year of pharmacy school at Midwestern University College of Pharmacy-Downers Grove. She holds the Event Chair position for Pharmacy and Pediatrics and is invested in learning more about women and children’s health. She is passionate about creating art in her free time as well as helping others heal through expressive therapy.

Kayla Mitzel, PharmD Candidate 2023, is currently in her second year of pharmacy school at Midwestern University College of Pharmacy – Downers Grove. She is serving as the President Elect for APhA-ASP, and the Member at Large for CPNP. Her hobbies include running and biking. 

Reviewed by Brooke Griffin, PharmD, BCACP.