Nextstellis®: A new drug update 

 

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

nextstellis packThe 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. 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. 

 

REFERENCES

  1. NEXTSTELLIS® (DRSP/E4): Now Available for Pregnancy Prevention. https://www.nextstellis.com/. Accessed June 25, 2021.
  2. Nextstellis (Drospirenone and Estetrol) [package insert]. U.S Food and Drug Administration website. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2021/214154s000lbl.pdf. Accessed April 2021. 
  3. Grossman Barr, Nancy. “Managing Adverse Effects of Hormonal Contraceptives.” American Family Physician, U.S. National Library of Medicine, 15 Dec. 2010, pubmed.ncbi.nlm.nih.gov/21166370/.
  4. Grandi G, Chiara Del Savio M, Lopes da Silva-Filho A, Facchinetti F. Estetrol (E4): the new estrogenic component of combined oral contraceptives. Taylor & Francis. https://www.tandfonline.com/doi/full/10.1080/17512433.2020.1750365. Published April 7, 2020. Accessed June 25, 2021.
  5. Singer, Christian F., et al. “Antiestrogenic Effects of the Fetal Estrogen Estetrol in Women with Estrogen-Receptor Positive Early Breast Cancer.” OUP Academic, Oxford University Press, 5 July 2014, academic.oup.com/carcin/article/35/11/2447/416699.
  6. Mithra Pharmaceuticals. “E4 Paves the Road towards a Revolutionary Era of Environmental FRIENDLY MEDICINES.” GlobeNewswire News Room, Mithra Pharmaceuticals, 10 Jan. 2020, http://www.globenewswire.com/news-release/2020/01/10/1968775/0/en/E4-Paves-the-Road-Towards-a-Revolutionary-Era-of-Environmental-Friendly-Medicines.html


About the Authors

AthinaAthina 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.

 

KaylaKayla 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.

Webinar Introduces Pharmacists to New Hormonal Contraceptives

New drugs are constantly being approved by the FDA, and it is important for practicing pharmacists to stay up to date on new contraceptives. There are now over 50 unique contraceptives available, and pharmacists need to be aware of these and incorporate them into their practices. Birth Control Pharmacist recently hosted a webinar that aimed to educate pharmacists, pharmacy staff members, and other healthcare providers to feel more comfortable with the new contraceptive options they could prescribe or dispense.

The faculty speaker, Shareen El-Ibiary, PharmD, BCPS, FCCP, is a professor and chair of the Department of Pharmacy Practice at Midwestern University, College of Pharmacy. She is also a consultant for Birth Control Pharmacist.

The program focused on three new hormonal contraceptives – Annovera, Twirla, and Slynd – along with one new nonhormonal contraceptive – Phexxi.

What is Annovera?

Annovera is a new contraceptive vaginal ring that contains segesterone and ethinyl estradiol. It is different from NuvaRing because it is used for 13 consecutive cycles, as opposed to just one cycle. It is not refrigerated.

What is Twirla?

Twirla is a new contraceptive patch that contains levonorgestrel and ethinyl estradiol. It is very similar to Xulane in terms of application, but Twirla has lower rates of headache, nausea, and breast tenderness.

What is Slynd?

Slynd is a new progestin-only oral contraceptive that contains drospirenone. In each pack of 28 tablets, there are 24 active tablets and four inactive tablets. The main benefit of Slynd over norethindrone is less opportunity for missed doses. Unlike norethindrone’s 3-hour window to take a dose, patients on Slynd have up to a 24-hour window to take a dose before it is considered a missed dose. Pharmacists need to be aware of the unique drug interactions associated with Slynd.

What is Phexxi?

Phexxi is a new prescription-only contraceptive gel that does not contain nonoxynol-9. Instead, it contains lactic acid, citric acid, and potassium bitartrate. Phexxi should be applied vaginally within one hour before each episode of intercourse. It should not be used by patients who have recurrent urinary tract infections or urinary tract abnormalities.

Dr. El-Ibiary wrapped up the program by reviewing patient cases, and she even demonstrated a patient interaction within a pharmacy. This helped bring the concepts from the lecture portion to life and allowed participants to practice incorporating these new hormonal contraceptive into their counseling and other practices.

Fortunately, if you missed the webinar, the video recording and materials are available for home study online at https://birthcontrolpharmacist.com/newhc/. The course material is available to all, with pharmacists having the opportunity to obtain Continuing Pharmacy Education credit. This material provides education to participants to increase their comfort in prescribing, dispensing, or counseling patients on the new contraceptive options available.

Participants provided feedback at the conclusion. Keep reading to see their positive reviews and gain a better idea of what to expect from the online course:

 “As a P1, I appreciate how Dr. El-Ibiary explained everything clearly. It helped me better understand the content and I now have a much better understanding of contraceptives.”

“Very practical, real-life patient case scenarios were used as effective teaching points.”

“Amazing presentation. Very informative and easy to follow.”

“Thank you for providing this CE! It was both helpful & thorough.”

New Hormonal Contraceptives Home Study CPE


Katie HoodAbout the Author

Katie Hood, PharmD Candidate is a pharmacy student in the Class of 2021 at Shenandoah University Bernard J. Dunn School of Pharmacy and Pharmaceutical Sciences. Katie completed an elective APPE rotation with Birth Control Pharmacist.

Meet Slynd: A Novel Progestin-Only Pill

What’s this new pill?

Slynd® is the new progestin-only oral contraceptive approved by the FDA in May 2019. This novel progestin-only pill (POP) contains drospirenone 4 mg in each active tablet, which is a higher dose than what is found in drospirenone-containing combined oral contraceptives (COCs). 

Table 1. Products with drospirenone.

Product Name

Medication Doses

Regimen

Yasmin, Zarah, Syeda, Ocella

Drospirenone 3 mg, ethinyl estradiol 30 mcg

21/7

Safyral

Drospirenone 3 mg, ethinyl estradiol 30 mcg, levomefolate calcium 451 mcg

21/7

Yaz, Gianvi, Loryna

Drospirenone 3 mg, ethinyl estradiol 20 mcg

24/4

Beyaz

Drospirenone 3 mg, ethinyl estradiol 20 mcg, levomefolate calcium 451 mcg

24/4

Slynd

Drospirenone 4 mg

24/4

This will be the second POP formulation available, in addition to the many norethindrone 0.35 mg products currently available.

What are the features of this new pill?

This pill provides pregnancy prevention with a 24/4 dose regimen. In the ongoing evolution of contraception, the goal has always been to improve efficacy as well as minimizing adverse events. Estrogen dose reduction and shortening of hormone-free intervals have been helpful to meet these goals. As a result, Slynd was developed with a 24/4 dose regimen which provides a more stable hormonal timeframe compared to traditional 21/7 dose regimens, achieving greater pituitary and ovarian suppression. For this reason, the 24/4 regimen has less hormone withdrawal effect and improves pelvic pain, headaches, breast tenderness, and bloating symptoms that are reported during the hormone-free days with 21/7 regimens.  

Slynd pill pack

Figure 1. Slynd pill pack containing 24 active pills and 4 inactive pills.

(Image credit: slynd.com)

Slynd also allows a 24-hour missed pill window which improves reliability and bleeding profiles in the event of a missed dose. One study compared two arms — one with four missed doses (four 24-hour delays) and the other with no missed dose during the cycle. Even with four missed doses in the cycle, there was adequate ovarian suppression and the same follicular size was observed in both arms.

Drospirenone inhibits ovulation by suppressing luteinizing hormone (LH) secretion. Additionally, by modifying cervical mucus, it reduces sperm transport and thus prevents fertilization. Unlike other conventional synthetic progestins, drospirenone has a similar profile to endogenous progesterone. As an analogue of 17-alpha spironolactone, drospirenone has anti-mineralocorticoid and anti-androgenic activity. Due to the anti-mineralocorticoid activity, it increases urinary sodium and serum aldosterone. Therefore, compared to other COCs causing fluid retention and edema, drospirenone has an ability to reduce blood pressure. 

 

Should we be worried about blood clots with drospirenone?

Drospirenone was first introduced to the market in combination with low dose ethinyl estradiol as a contraceptive well suited for women with premenstrual dysphoric disorder (PMDD), moderate acne, polycystic ovarian syndrome and hirsutism. 

While the FDA is concerned about the potential correlation between contraceptives containing drospirenone and blood clots, the overall result of two prospective multicenter phase III studies reported no single case of venous thromboembolism (VTE) in patients who used POP. FDA has funded a study to investigate the correlation, and still is reviewing other clinical trials. In 2011, the FDA reported that “preliminary results of the FDA-funded study suggest an approximately 1.5-fold increase in the risk of blood clots for women who use drospirenone-containing birth control pills compared to users of other hormonal contraceptives.” 

Other studies have shown use of drospirenone-containing COCs was not associated with increased risk of thromboembolic events compared to other COCs containing other progestins. Due to data limitations, the causality is still unclear, and FDA will provide updates once available. 

While there is an increase in the relative risk of this rare adverse event with COCs containing drospirenone, the incidence is still very low and much lower than pregnancy and postpartum periods. ACOG’s Committee on Gynecologic Practice has concluded that the risk of thromboembolism in patients who use drospirenone-containing COCs is very low.  

It is unknown whether Slynd increases the risk of VTEs, however, any potential risk with this POP is expected to be lower than COCs containing drospirenone. 

 

Which patients should not use this pill?

Drospirenone is contraindicated in women with positive or unknown antiphospholipid antibodies, ischemic heart disease, stroke, current or history of breast cancer, hepatocellular adenoma, malignant hepatoma, and severe hepatitis. Clinicians should use this medication with caution in patients who are taking other medications that can predispose them to hyperkalemia, or monitor potassium level.

The drug interaction profile is similar to drospirenone-containing COCs. Although drospirenone is metabolized independently of P450 enzymes, it is a minor substrate of CYP3A4. It is recommended to avoid use in patients taking strong 3A4 inhibitors to prevent hyperkalemia. Strong P450 and P-glycoprotein transporter inhibitors and inducers can affect the serum concentration, efficacy, and adverse effects. 

 

What’s the bottom line for place in therapy?

In conclusion, Slynd can be used in most patients and will be an important option for patients with contraindications to estrogen — including history of high blood pressure or smoking above age 35 — PMDD, as well as patients desiring contraception without androgenic effects, such as those with acne or polycystic ovary syndrome (PCOS).

 

References:

  1. Mishell DR. “YAZ and the Novel Progestin Drospirenone.” The Journal of Reproductive Medicine 2008.
  2. Machado RB, et al. “Drospirenone/Ethinylestradiol: A Review on Efficacy and Noncontraceptive Benefits.” Womens Health 2011;7(1)19–30.
  3. Bachmann G, Kopacz S. “Drospirenone/Ethinyl Estradiol 3 Mg/20 Mug (24/4 Day Regimen): Hormonal Contraceptive Choices – Use of a Fourth-Generation Progestin.” Patient Preference and Adherence, 2009 
  4. Palacios S, et al. “Multicenter, Phase III Trials on the Contraceptive Efficacy, Tolerability and Safety of a New Drospirenone‐Only Pill.” Acta Obstetricia Et Gynecologica Scandinavica 2019.
  5. Center for Drug Evaluation and Research. “Risk of Blood Clots with Birth Control Pills Containing Drospirenone.” FDA Website Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-possible-increased-risk-blood-clots-birth-control.
  6. American College of Obstetricians and Gynecologists. Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. Committee Opinion No. 540. Obstet Gynecol 2012;120:1239–42. Available at: https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Risk-of-Venous-Thromboembolism.
  7. Drugs.com. Exeltis USA, Inc. Announces the Approval of Slynd (drospirenone), the First and Only Progestin-Only Pill Providing Pregnancy Prevention with a 24/4 Dosing Regimen and 24-hour Missed Pill Window. 2019. [online]
  8. Slynd (drospirenone) [prescribing information]. Florham Park, NJ; Exeltis USA, Inc.; May 2019.
  9. Duijkers IJ, Heger-Mahn D, Drouin D, Colli E, Skouby S. Maintenance of ovulation inhibition with a new progestogen-only pill containing drospirenone after scheduled 24-h delays in pill intake. Contraception 2016;93(4):303–309.
  10. CDC. US Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65Available at: https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/appendixc_tableC1.html

Lida Binesheian - Slynd Article on Birth Control Pharmacist

About the Author:

Lida Binesheian, PharmD, CACP is a Clinical Pharmacist and Certified Anticoagulation Care Provider based in Austin, Texas.