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.

Can the NuvaRing be used for 4 weeks instead of the usual 3 weeks?

nuvaring birth control pharmacistNuvaRing was named one of the best healthcare inventions of the year by TIME Magazine in 2001. It was a new birth control option that allowed women to avoid taking daily pills, receiving injections, or inserting a hormonal implant. The first contraceptive vaginal ring (CVR) approved in the U.S., NuvaRing is a flexible, self-administered, transparent ring that contains progestin (etonogestrel) and estrogen (ethinyl estradiol). These hormones are released continuously (average 0.12 mg/day etonogestrel and 0.015 mg/day ethinyl estradiol) when inserted in the vagina. NuvaRing remains a popular method of hormonal contraception today.

After being on the market for almost 2 decades, vaginal ring use has increased and use can be tailored to fit patients’ needs, such as skipping the monthly withdrawal bleed. According to the manufacturer’s prescribing information, maximum effectiveness is achieved when the ring is inserted in the vagina continuously for 3 weeks and then removed for one week to allow for a monthly withdrawal bleed — mimicking the natural menstrual cycle. However, prescribers may write prescriptions with different instructions for use. Continuous use regimens may be prescribed to insert a new vaginal ring every 3 or 4 weeks without a ring-free week. Patients that use a continuous use regimen (omitting a ring-free week) will likely not experience a withdrawal bleed. However, breakthrough spotting or unscheduled bleeding may be experienced with continuous use regimens.

What is the evidence behind using the vaginal ring for four weeks instead of the usual three weeks?

The manufacturer states NuvaRing is still an effective hormonal contraception if inserted for 4 weeks (instead of the usual three weeks), but the manufacturer recommends removing it for a ring-free week before inserting a new ring for maximum contraceptive effectiveness. Ovulation inhibition to prevent pregnancy is maintained with insertion of the CVR for up to 4 weeks. However, the manufacturer recommends ruling out pregnancy for placements longer than 4 weeks before inserting a new ring.

Some systemic side effects of the CVR are comparable to oral contraceptives with similar incidence of headaches and weight gain. However, CVRs have an increased risk for local vaginal side effects like vaginitis (12.2% in CVR versus 6.8% in oral contraceptives) and vaginal discharge (4.8% in CVR versus 1.6% in oral contraceptives). Patients using CVR report less nausea and breast tenderness when compared with patients using oral contraceptives. Side effects may be related to the serum level differences between CVRs and oral contraceptives. Bioavailability of ethinyl estradiol are similar between CVR versus oral contraceptives at 55.6% versus 43% to 55%, respectively. However, the bioavailability of the progestin in CVRs are almost double at 100%, compared to 64% in oral contraceptives. The NuvaRing package insert includes precautions for carbohydrate and lipid metabolic effects, high blood pressure, headaches, uterine bleeding, vascular risks, liver disease, and Toxic Shock Syndrome.

While a potential risk, Toxic Shock Syndrome has rarely been reported with CVR use. The table below summarizes the evidence found in clinical studies of extended CVR use.

Table 1. Summary of clinical studies of extended regimens of the contraceptive vaginal ring (CVR).

Study Title

(PubMed ID, Year)

Purpose Design (Study size) Results Conclusion
Extended regimens of the combined contraceptive vaginal ring containing etonogestrel and ethinyl estradiol: effects on lipid metabolism

21757057 (2011)

To evaluate lipid changes with continuous CVR use for one year Prospective cohort (n=75) of continuous use for 3 months, followed by one ring-free week Significant increase in total triglycerides Extended CVR use may cause lipid changes, but this side effect is similar to oral or parenteral estrogen use
Extended regimens of the combined contraceptive vaginal ring: evaluation of clinical aspects

20159178 (2010)

To evaluate symptoms, body weight, and blood pressure changes with continuous CVR use for one year Prospective cohort (n=75) of continuous use for 3 months, followed by one ring-free week Less irritability, less dysmenorrhea, increased body weight (within an expected range), no changes in blood pressure Extended CVR use is well-tolerated with some non-contraceptive benefits (mood, less painful menstruation)
Extended regimens of the combined contraceptive vaginal ring: cycle control

19835716 (2009)

To compare menstrual patterns of women using extended CVR or oral contraceptives Prospective cohort (n=75 on CVR, 75 on oral) of continuous use for 3 months, followed by one contraceptive-free week Significant decrease in total days of bleeding and spotting for both methods, slightly lower for oral route Continuous oral use may result in less menstruation, but CVR offers more predictable menstrual cycle control with less unscheduled bleeding
Frequency and management of breakthrough bleeding with continuous use of the transvaginal contraceptive ring: a randomized controlled trial

18757653 (2008)

To evaluate bleeding patterns with continuous CVR Prospective cohort (n=74) on CVR for continuous 6 months. Group 1 did not have ring-free days. Group 2 instructed to remove CVR for 4 days if bleeding occurs, and reinsert the same ring Group 2 experienced less days of bleeding compared to Group 1 A 4-day ring-free period helped resolve breakthrough bleeding better compared to continuous ring use without ring-free periods

 

References:

  1. Agile Therapeutics. Women’s Health Specialty Pharmaceutical Company [Internet]. Jefferies; 2016. Available from: Link
  2. Barreiros FA, Guazzelli CAF, Barbosa R, Torloni MR, Barbieri M, Araujo FF. Extended regimens of the combined contraceptive vaginal ring containing etonogestrel and ethinyl estradiol: effects on lipid metabolism. Contraception. 2011;84(2):155–9.
  3. Barreiros FA, Guazzelli CAF, Barbosa R, Assis FD, Araújo FFD. Extended regimens of the contraceptive vaginal ring: evaluation of clinical aspects. Contraception. 2010;81(3):223–5.
  4. Best Inventions of 2001 [Internet]. Time. Time Inc.; 2001. Available from: Link.
  5. Guazzelli CAF, Barreiros FA, Barbosa R, Araújo FFD, Moron AF. Extended regimens of the vaginal contraceptive ring: cycle control. Contraception. 2009;80(5):430–5.
  6. Kerns J, Darney P. Contraceptive Vaginal Ring. In: Schreiber C, editor. UpToDate. [Internet].: UpToDate; 2017. Available from Link.
  7. Merck & Co. NuvaRing: Highlights of Prescribing Information. 2018. Available from: Link.
  8. NuvaRing. DrugDex Evaluations. In: Micromedex 2.0 [Internet]. Ann Arbor, MI: Truven Health Analytics. c2018. Available from Link
  9. Sulak PJ, Smith V, Coffee A, Witt I, Kuehl AL, Kuehl TJ. Frequency and Management of Breakthrough Bleeding With Continuous Use of the Transvaginal Contraceptive Ring. Obstetrics & Gynecology. 2008;112(3):563–71.

Christine YuAbout the Author:

Christine Yu is a fourth-year pharmacy student at the University of California San Francisco School of Pharmacy in San Francisco, California.