Ethinylestradiol/etonogestrel explained

Ethinylestradiol/etonogestrel, sold under the brand names NuvaRing among others, is a hormonal vaginal ring used for birth control and to improve menstrual symptoms. It contains ethinylestradiol, an estrogen, and etonogestrel, a progestin.[1] It is used by insertion into the vagina. Pregnancy occurs in about 0.3% of women with perfect use and 9% of women with typical use.[2]

Common side effects include irregular vaginal bleeding, nausea, sore breasts, vaginitis, mood changes, and headache. Rare but serious side effects may include blood clots, toxic shock syndrome, anaphylaxis, gallstones, and liver problems.[3] Use is not recommended in those who both smoke and are over the age of 35.[3] While use in pregnancy is not recommended, such use has not been found to be harmful to the baby.[3] Use during breastfeeding is typically not recommended as it may decrease the milk supply.[3] It mainly works by decreasing gonadotropins thereby stopping ovulation.[3]

The combination was approved for medical use in the United States in 2001.[1] It is available as a generic medication in the United Kingdom.[4] In 2021, it was the 198th most commonly prescribed medication in the United States, with more than 2million prescriptions.[5] [6]

Medical use

The ring is placed into the vagina for a three-week period, then removal of the ring for one week, during which the user will experience a menstrual period. The break week is comparable to the placebo week for combined oral birth control pills ("the Pill"), and the birth control effect is maintained during this period. Extended use regimens (seven-week, quarterly, or annual) involving back-to-back use of (2, 4, or 17) rings have been studied in clinical trials, but are not currently approved.[7] [8] [9]

Insertion of the ring is comparable to insertion of other vaginal rings. The muscles of the vagina keep NuvaRing securely in place, even during exercise or sex. Women can check the birth control ring periodically with their finger. In rare instances, NuvaRing may fall out during sexual intercourse, while straining before or during a bowel movement, or while removing a tampon.[10] [11]

In the case of accidental expulsion, the manufacturer recommends rinsing the ring with lukewarm water before reinserting. If not done correctly, the risk of pregnancy is increased. Birth control efficacy is reduced if the ring is removed, accidentally expelled, or left outside of the vagina for more than three hours. If left outside of the vagina for more than three hours, the device is to be rinsed and reinserted immediately. If this occurs, the manufacturer recommends that a backup method of birth control be used until the ring has been used continuously for a subsequent seven days.[10] [11]

Benefits

The benefits of the ring include:

Contraindications

The contraceptive vaginal ring is contraindicated for a risk of blood clots. This is because it contains the hormone etonogestrel, the active metabolite of the prodrug desogestrel. It is a third-generation contraceptive.

A study in The BMJ, with over 1.6 million women, found that users of vaginal rings with ethinylestradiol and etonogestrel have a 6.5 times increased risk of venous thrombosis compared to non-users.[18] Epidemiological studies have shown that oral contraceptives that contain desogestrel can increase the risk of blood clots (venous thrombosis) by 1.5 to 2.4 times the risk of second-generation oral contraceptives.[19] Second-generation oral contraceptives do not contain desogestrel. Hormones are released continuously from NuvaRing, thus peak and total estrogen and progestin doses are lower than with combined oral contraceptives, but what effect this has on the risk of blood clots has not been established.[11]

NuvaRing also has the cardiovascular contraindications associated with combined oral contraceptives, such as stroke and heart attack. These risks have been shown to be much greater if combined with other risk factors such as smoking, recent surgery, a history of cardiovascular disease, or women over 40 years old.[11]

NuvaRing should not be used while breastfeeding. The hormones may pass to the baby through the milk, and it may decrease milk production.[20]

Side effects

In two large studies, over a one-year period, 15.1% of users discontinued NuvaRing because of adverse events. Device-related adverse events (foreign object sensation, sexual problems, or expulsion) were the most frequently reported adverse events that resulted in discontinuation (by 2.5% of users). Device-related adverse events were reported at least once during the one-year study period by 4.4% of NuvaRing users.[16]

The most common adverse events reported by 5 to 14% of the 2501 women who used NuvaRing in five clinical trials were: vaginitis (14.1%), headache (9.8%), upper respiratory tract infection (8.0%), leukorrhea (5.8%), sinusitis (5.7%), nausea (5.2%), weight gain (4.9%) and hair loss .[11] [21] [22] NuvaRing is weight neutral.[23] [24] Additional side effect information (including, but not limited to, severe blood clots) is provided in the NuvaRing full prescribing information.[11] [22] Breakthrough bleeding occurs in 2.0 to 6.4% of NuvaRing users.[25]

Blood clots

The vaginal ring with ethinylestradiol and etonogestrel increases the risk of venous blood clots 6.5 times compared to non-users of hormonal birth control.[26] This is similar to the risk of blood clots with combination birth control pills, which range between 3 times to 14 times the risk.[27] As such, birth control vaginal rings do not necessarily appear to pose a lower risk of thrombosis than do birth control pills. Additionally pregnancy and the period immediately following pregnancy is associated with a high risk of blood clots.[3]

Mechanism of action

Like all combined hormonal contraceptives, NuvaRing works primarily by preventing ovulation. A secondary mechanism of action is inhibition of sperm penetration by changes in the cervical mucus. Hormonal contraceptives also have effects on the endometrium that theoretically could affect implantation; however, no scientific evidence indicates that prevention of implantation actually results from their use.[28] NuvaRing should not be used if a woman is pregnant.

NuvaRing delivers 120 μg of etonogestrel (a progestin) and 15 μg of ethinylestradiol (an estrogen) each day of use.

Society and culture

Restrictions on use

In July 2014, CTV News reported that Merck Canada Inc. stated that women who are over 35 and smoke should not use the NuvaRing. In addition to this group of women, women who have any of the following conditions also should not use the NuvaRing: abnormal blood-fat levels, clotting disorders, diabetes, heart disease, high blood pressure, migraine headaches with vision problems or "constant stomach pain caused by pancreatic dysfunction along with high levels of fats in the blood".[29]

Lawsuits

Lawsuits were filed in the US against Merck alleging it concealed health risks associated with the product.[30] These were settled for $100 million in 2014.[31]

In March 2008, the first lawsuit was filed against the manufacturers, distributors, and marketers of NuvaRing. The plaintiff alleged that these companies concealed the health risks associated with using the device, which is claimed to have caused the death of the plaintiff's wife.[32] Subsequent plaintiffs alleged multiple problems with the advertising of NuvaRing and that they downplayed its risks of injury and death.[33] The company denied these allegations.[33]

The first bellwether trial, selected from a pool of federal lawsuits, was scheduled to begin in April 2014.[34] In February 2014, however, Merck & Co announced that it was ready to settle the NuvaRing lawsuits for $100 million. At that time, there were more than 1,850[35] lawsuits and the settlement was initially estimated pay about $58,000 per complaint.[36] Approval of the settlement required 95% of the plaintiffs to agree to settle in March 2014,[35] otherwise Merck could retract their offer.[37] In June 2014, US District Judge Rodney W. Sippel approved the $100 million settlement. About 3,800 claimants would share the settlement.[38]

History

NuvaRing was first approved in The Netherlands in February 2001, then by the European Union in June 2001, and in the United States by the US Food and Drug Administration (FDA) in October 2001.[39] [40]

NuvaRing was first marketed in the United States in July 2002,[41] followed by a number European countries since then.[42]

Research

A study by Danish researcher Dr. Øjvind Lidegaard in 2012 with 1.6 million women found a 6.5 times increase in the likelihood of venous thromboembolism when compared to users of non-hormonal based birth control. In Canada, Lidegaard's study led to a change in labeling warning of increased risk of blood clots, but not in the United States.[18]

See also

External links

Notes and References

  1. Web site: Ethinyl Estradiol and Etonogestrel (Professional Patient Advice) . Drugs.com . April 19, 2019 .
  2. Book: Trussell J . 2011. Contraceptive efficacy. Hatcher RA, Trussell J, Nelson AL, Cates Jr W, Kowal D, Policar MS . Contraceptive technology. 20th revised. New York. Ardent Media. 978-1-59708-004-0. 0091-9721. 781956734. 779–863. Web site: Table 3–2 Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception, and the percentage continuing use at the end of the first year. United States. . https://web.archive.org/web/20170215224018/http://www.contraceptivetechnology.org/wp-content/uploads/2013/09/CTFailureTable.pdf . February 15, 2017 .
  3. Web site: NuvaRing - FDA prescribing information, side effects and uses . Drugs.com . April 19, 2019 .
  4. Book: British National Formulary: BNF 76. 2018 . Pharmaceutical Press . 9780857113382 . 780 . 76th.
  5. Web site: The Top 300 of 2021 . ClinCalc . January 14, 2024 . January 15, 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  6. Web site: Ethinyl Estradiol ; Etonogestrel - Drug Usage Statistics . ClinCalc . January 14, 2024.
  7. Web site: Organon . September 15, 2005 . NuvaRing is effective and well tolerated in extended use - Most women would like to decrease their number of periods a year . April 12, 2007 . Organon International . https://archive.today/20061018185120/http://www.organon.com/news/press_releases/2005_09_15_nuvaring_is_effective_and_well_tolerated_in_extended_use.asp . October 18, 2006 . dead .
  8. Miller L, Verhoeven CH, Hout J . Extended regimens of the contraceptive vaginal ring: a randomized trial . Obstetrics and Gynecology . 106 . 3 . 473–482 . September 2005 . 16135576 . 10.1097/01.AOG.0000175144.08035.74 . 46164922 .
  9. Barreiros FA, Guazzelli CA, de Araújo FF, Barbosa R . Bleeding patterns of women using extended regimens of the contraceptive vaginal ring . Contraception . 75 . 3 . 204–208 . March 2007 . 17303490 . 10.1016/j.contraception.2006.10.009 .
  10. Web site: Organon . NuvaRing: Common Questions: Will NuvaRing fall out? . July 6, 2009 . Organon International . July 6, 2012 . https://web.archive.org/web/20120706050604/http://www.nuvaring.com/Consumer/commonQuestions/index.asp#201886 . dead .
  11. Web site: Organon . August 2005 . NuvaRing - US Prescribing Information . April 12, 2007 . https://web.archive.org/web/20070323231737/http://www.nuvaring.com/Authfiles/Images/309_76063.pdf . March 23, 2007 . Organon International . dead .
  12. Book: Hatcher RA, Nelson A . Combined Hormonal Contraceptive Methods . 2004 . Hatcher RA, Trussell J, Stewart F, Cates Jr W, Stewart GK, Guest F, Kowal D . Contraceptive Technology . 18th rev. . 391–460 . New York . Ardent Media . 978-0-9664902-5-1.
  13. Web site: Organon . NuvaRing: Questions patients may have: Will my partner or I feel NuvaRing? . July 16, 2007 . https://web.archive.org/web/20070225020833/http://www.nuvaring.com/HCP/PatientSupport/PotentialQuestions/index.asp#76125 . February 25, 2007 . Organon International . dead .
  14. Web site: Organon . NuvaRing: Knowing the benefits: Low dose of hormones . April 12, 2007 . https://web.archive.org/web/20061118202028/http://www.nuvaring.com/HCP/KnowingTheBenefits/lowerBloodLevelsOfEstrogen/index.asp . November 18, 2006 . Organon International . dead .
  15. van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC . Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive . Contraception . 72 . 3 . 168–174 . September 2005 . 16102549 . 10.1016/j.contraception.2005.03.005 .
  16. Dieben TO, Roumen FJ, Apter D . Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring . Obstetrics and Gynecology . 100 . 3 . 585–593 . September 2002 . 12220783 . 10.1016/S0029-7844(02)02124-5 . 23769913 .
  17. Book: Speroff L, Darney PD . 2005 . Vaginal and Transdermal Estrogen-Progestin Contraception . A Clinical Guide for Contraception . 4th . 153–164 . Philadelphia . Lippincott Williams & Wilkins . 978-0-7817-6488-9.
  18. News: Sabrina S . Side Effects May Include Death: The Story Of The Biggest Advance In Birth Control Since The Pill. The Huffington Post. December 19, 2013. December 18, 2013.
  19. Web site: Walker MB, Bussey HI . Should 3rd Generation Birth Control Pills be Banned? - Petition to Ban 3rd Generation OCs due to Increased Clotting Risk . 2007 . September 30, 2008 . https://web.archive.org/web/20080913173413/http://www.clotcare.com/clotcare/oralcontraceptivebloodclots.aspx . September 13, 2008 . dead .
  20. Web site: emedtv.com. December 28, 2016. March 4, 2016. https://web.archive.org/web/20160304002413/http://women.emedtv.com/nuvaring/nuvaring-and-breastfeeding.html. dead.
  21. Web site: FDA . 2001 . NuvaRing NDA 21-187 Medical Review Part 2 . . 51, 53 . September 14, 2007 . https://web.archive.org/web/20070926084032/https://www.fda.gov/cder/foi/nda/2001/21-187_NuvaRing_medr_P2.pdf . September 26, 2007 . Food and Drug Administration . dead .
  22. Web site: Organon . NuvaRing: Questions patients may have: What are the side effects associated with NuvaRing? . September 14, 2007 . https://web.archive.org/web/20081025045250/http://www.nuvaring.com/HCP/PrescribingNuvaRing/QuestionsPatientsMayHave/index.asp#75996 . October 25, 2008 . Organon International . dead .
  23. Web site: Organon . NuvaRing: Questions patients may have: Does NuvaRing cause weight gain? . September 14, 2007 . https://web.archive.org/web/20081025045250/http://www.nuvaring.com/HCP/PrescribingNuvaRing/QuestionsPatientsMayHave/index.asp#75996 . October 25, 2008 . Organon International . dead .
  24. Bjarnadóttir RI, Tuppurainen M, Killick SR . Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol . American Journal of Obstetrics and Gynecology . 186 . 3 . 389–395 . March 2002 . 11904596 . 10.1067/mob.2002.121103 .
  25. Roumen FJ . Review of the combined contraceptive vaginal ring, NuvaRing . Therapeutics and Clinical Risk Management . 4 . 2 . 441–451 . April 2008 . 18728840 . 2504064 . 10.2147/tcrm.s1964 . free .
  26. Lidegaard O, Nielsen LH, Skovlund CW, Løkkegaard E . Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10 . BMJ . 344 . e2990 . May 2012 . 22577198 . 3349780 . 10.1136/bmj.e2990 .
  27. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR . The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study . BMJ . 339 . b2921 . August 2009 . 19679614 . 2726929 . 10.1136/bmj.b2921 .
  28. Rivera R, Yacobson I, Grimes D . The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices . American Journal of Obstetrics and Gynecology . 181 . 5 Pt 1 . 1263–1269 . November 1999 . 10561657 . 10.1016/S0002-9378(99)70120-1 .
  29. News: The Canadian Press. NuvaRing maker advises some women to avoid using product. August 8, 2014. CTV News. July 31, 2014.
  30. News: Mencimer S . Is NuvaRing Dangerous?. June 30, 2013. Mother Jones. 2009.
  31. News: Merck to Dole Out $100 Million in NuvaRing Settlement . April 19, 2019 . Time . February 7, 2014 .
  32. News: Cotton M . Schering-Plough, Akzo Nobel sued over NuvaRing contraceptive device . Thomson Financial News . Forbes . March 20, 2008 . https://archive.today/20080330235629/http://www.forbes.com/feeds/afx/2008/03/20/afx4796911.html . dead . March 30, 2008 . May 6, 2008.
  33. News: Edwards J . At Merck, an Undercover Video and 40 Deaths Plague Nuvaring Birth Control Brand . June 5, 2014 . . April 19, 2014 . https://web.archive.org/web/20140310003731/http://www.cbsnews.com/news/at-merck-an-undercover-video-and-40-deaths-plague-nuvaring-birth-control-brand/ . March 10, 2014 . live .
  34. Web site: Case: 4:08-md-01967-RWS (Nuvaring Products Liability Litigation). November 22, 2013.
  35. "NuvaRing's $100 Million Settlement Deadling is Monday", The Detroit Free Press, March 9, 2014, page 9A
  36. News: Merck to settle NuvaRing lawsuits for $100 mln -media report. February 7, 2014. Reuters. February 6, 2014.
  37. News: Feeley J, Voreacos D . Merck to Pay $100 Million NuvaRing Pact If Women Join. Thomson Financial News . Forbes . February 7, 2014 . February 6, 2014.
  38. News: Salter J . $100 Million NuvaRing Settlement Finalized . June 5, 2014 . . June 5, 2014 . https://web.archive.org/web/20140605225421/http://abcnews.go.com/US/wireStory/100-million-nuvaring-settlement-finalized-24013800 . June 5, 2014 . live .
  39. News: Doyle J . FDA approved NuvaRing despite experts' safety concerns. March 11, 2014. St. Louis Post-Dispatch. March 1, 2014.
  40. Web site: Food and Drug Administration (United States) . 2001 . NuvaRing NDA 21-187 Correspondence Part 1 . . 8 . April 12, 2007 . https://web.archive.org/web/20070926084031/https://www.fda.gov/cder/foi/nda/2001/21-187_NuvaRing_corres_P1.pdf . September 26, 2007 . dead . Food and Drug Administration (United States) .
  41. Web site: Organon . July 16, 2002 . NuvaRing world's first vaginal birth control ring, first launch now in the US . September 14, 2008 . Organon International . dead . https://web.archive.org/web/20061130061025/http://www.nuvaring.com/Authfiles/Images/309_76087.pdf . November 30, 2006 .
  42. Web site: Organon's Once-a-Month Contraceptive Ring, NuvaRing(R) Completes European Authorization. PR Newswire. June 30, 2013.

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