Vaginal ring application (step 1)
|Trade names||NuvaRing, others|
|AHFS/Drugs.com||Micromedex Detailed Consumer Information|
Ethinylestradiol/etonogestrel (brand names NuvaRing) is a contraceptive vaginal ring containing the estrogen ethinylestradiol and the progestin etonogestrel which is marketed in the United States and Europe.
A study found that users of vaginal rings with ethinylestradiol and etonogestrel have a 6.5 times increased risk of venous thrombosis compared to non-users. This is commensurate with the risk of thrombosis due to the use of combination birth control pills, which in studies ranged between 2.9 times to 13.7 times the risk. As such, contraceptive vaginal rings do not necessarily appear to pose a lower risk of thrombosis than do birth control pills.
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 contraceptive pills ("the Pill"), and the contraceptive 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.
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 contraceptive 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.
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. Contraceptive 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 contraception be used until the ring has been used continuously for a subsequent seven days.
The benefits of the ring include:
- once-a-month self-administered use offering convenience, ease of use and privacy (most users and most partners do not feel the ring, and of those who do, most do not object to it)
- lower estrogen exposure than with combined oral contraceptive pills or the contraceptive patch Ortho Evra.
- a low incidence of estrogenic side effects such as nausea and breast tenderness
- a low incidence of irregular bleeding despite its lower estrogen dose
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. 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. Second-generation oral contraceptives do not contain desogestrel. Hormones are released continuously from NuvaRing, thus peak and total estrogen and progestin doses are significantly lower than with combined oral contraceptives, but what effect this has on the risk of blood clots has not been established.
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.
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.
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%), and weight gain (4.9%). NuvaRing is weight neutral. Additional side effect information (including, but not limited to, severe blood clots) is provided in the NuvaRing full prescribing information. Breakthrough bleeding occurs in 2.0 to 6.4% of NuvaRing users.
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. NuvaRing should not be used if a woman is pregnant.
Society and culture
Restrictions on use
On July 31, 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".
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. Subsequent plaintiffs alleged multiple problems with the advertising of NuvaRing and that they downplayed its risks of injury and death. The company denied these allegations.
The first bellwether trial, selected from a pool of federal lawsuits, was scheduled to begin on April 7, 2014. On February 6, 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 lawsuits and the settlement was initially estimated pay about $58,000 per complaint. Approval of the settlement required 95% of the plaintiffs to agree to settle by the end of the day, March 10, 2014, otherwise Merck could retract their offer. On June 5, 2014 US District Judge Rodney W. Sippel approved the $100 million settlement. About 3,800 claimants would share the settlement.
NuvaRing was first approved in The Netherlands on February 14, 2001, then by all 14 other countries then in the European Union on June 12, 2001, and in the United States by the U.S. Food and Drug Administration (FDA) on October 3, 2001. NuvaRing was first marketed in the United States in July 2002, followed by a number European countries since then. In March 2007, Organon announced the market launch of NuvaRing in Australia, bringing the total number of countries where NuvaRing is available to 32. 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.
- "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 22 December 2016.
- Lidegaard, Øjvin; Øjvind Lidegaard; Lars Hougaard Nielsen; Charlotte Wessel Skovlund; Ellen Løkkegaard (May 2012). "Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10". BMJ. 344: 1–9. doi:10.1136/bmj.e2990. PMID 22577198. Retrieved 30 June 2013.
- Vlieg, A van Hylckama; F M Helmerhorst; J P Vandenbroucke; C J M Doggen; F R Rosendaal (August 2009). "The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study". BMJ. 339. doi:10.1136/bmj.b2921. Retrieved 23 Dec 2013.
- Mencimer, Stephanie (2009). "Is NuvaRing Dangerous?". Mother Jones. Retrieved 30 June 2013.
- "New NuvaRing Blood-Clotting Lawsuit Allegations Update: Resource4thePeople Reports Lawsuits Continue to Be Filed and Trial on Track". WRCB TV. 2013. Retrieved 30 June 2013.
- Doyle, Jim (1 March 2014). "FDA approved NuvaRing despite experts' safety concerns". St. Louis Post-Dispatch. Retrieved 11 March 2014.
- 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". Retrieved 2007-04-12.
- Miller L, Verhoeven CH, Hout J (2005). "Extended regimens of the contraceptive vaginal ring: a randomized trial". Obstet Gynecol. 106 (3): 473–82. doi:10.1097/01.AOG.0000175144.08035.74. PMID 16135576.
- Barreiros FA, Guazzelli CA, de Araujo FF, Barbosa R (2007). "Bleeding patterns of women using extended regimens of the contraceptive vaginal ring". Contraception. 75 (3): 204–8. doi:10.1016/j.contraception.2006.10.009. PMID 17303490.
- Organon. "NuvaRing: Common Questions: Will NuvaRing fall out?". Retrieved 2009-07-06.
- Organon (August 2005). "NuvaRing - US Prescribing Information" (PDF). Archived from the original (PDF) on 2007-03-23. Retrieved 2007-04-12.
- Hatcher, Robert A.; Nelson, Anita (2004). "Combined Hormonal Contraceptive Methods". In Hatcher, Robert A.; et al. Contraceptive Technology (18th rev. ed.). New York: Ardent Media. pp. 391–460. ISBN 0-9664902-5-8.
- Dieben TO, Roumen FJ, Apter D (2002). "Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring". Obstet Gynecol. 100 (3): 585–93. doi:10.1016/S0029-7844(02)02124-5. PMID 12220783.
- Organon. "NuvaRing: Questions patients may have: Will my partner or I feel NuvaRing?". Archived from the original on 2007-02-25. Retrieved 2007-07-16.
- Organon. "NuvaRing: Knowing the benefits: Low dose of hormones". Archived from the original on 2006-11-18. Retrieved 2007-04-12.
- van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC (2005). "Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive". Contraception. 72 (3): 168–74. doi:10.1016/j.contraception.2005.03.005. PMID 16102549.
- Speroff, Leon; Darney, Philip D. (2005). "Vaginal and Transdermal Estrogen-Progestin Contraception". A Clinical Guide for Contraception (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 153–164. ISBN 0-7817-6488-2.
- Sabrina, Siddiqui (2013-12-18). "Side Effects May Include Death: The Story Of The Biggest Advance In Birth Control Since The Pill". The Huffington Post. Retrieved 19 December 2013.
- Marie B. Walker & Henry I. Bussey, Pharm.D., FCCP, FAHA (2007). "Should 3rd Generation Birth Control Pills be Banned? - Petition to Ban 3rd Generation OCs due to Increased Clotting Risk". Retrieved 2008-09-30.
- FDA (2001). "NuvaRing NDA 21-187 Medical Review Part 2" (PDF). pp. 51, 53. Archived from the original (PDF) on 2007-09-26. Retrieved 2007-09-14.
- Organon. "NuvaRing: Questions patients may have: What are the side effects associated with NuvaRing?". Archived from the original on 2007-09-27. Retrieved 2007-09-14.
- Organon. "NuvaRing: Questions patients may have: Does NuvaRing cause weight gain?". Archived from the original on 2007-09-27. Retrieved 2007-09-14.
- Bjarnadóttir RI, Tuppurainen M, Killick SR (2002). "Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol". Am J Obstet Gynecol. 186 (3): 389–195. doi:10.1067/mob.2002.121103. PMID 11904596.
- Review of the combined contraceptive vaginal ring, NuvaRing. by Frans Jme Roumen. Therapeutics and Clinical Risk Management 05/2008; 4(2):441-51.
- Rivera R, Yacobson I, Grimes D (1999). "The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices". Am J Obstet Gynecol. 181 (5 Pt 1): 1263–9. doi:10.1016/S0002-9378(99)70120-1. PMID 10561657.
- The Canadian Press (31 July 2014). "NuvaRing maker advises some women to avoid using product". CTV News. Retrieved 8 August 2014.
- Cotton, Mark (2008-03-20). "Schering-Plough, Akzo Nobel sued over NuvaRing contraceptive device". Thomson Financial News. Forbes.com. Retrieved 2008-05-06.
- Edwards, Jim (19 April 2014). "At Merck, an Undercover Video and 40 Deaths Plague Nuvaring Birth Control Brand". CBS News. Archived from the original on 5 June 2014. Retrieved 5 June 2014.
- "Case: 4:08-md-01967-RWS (Nuvaring Products Liability Litigation)" (PDF). Retrieved 22 November 2013.
- "NuvaRing's $100 Million Settlement Deadling is Monday", The Detroit Free Press, March 9, 2014, page 9A
- "Merck to settle NuvaRing lawsuits for $100 mln -media report". Reuters. 6 February 2014. Retrieved 7 February 2014.
- Feeley, Jef and David Voreacos (2014-02-07). "Merck to Pay $100 Million NuvaRing Pact If Women Join". Thomson Financial News. Forbes.com. Retrieved 2014-02-06.
- Salter, Jim (5 June 2014). "$100 Million NuvaRing Settlement Finalized". ABC News. Archived from the original on 5 June 2014. Retrieved 5 June 2014.
- Food and Drug Administration (United States) (2001). "NuvaRing NDA 21-187 Correspondence Part 1," (PDF). p. 8. Archived from the original (PDF) on 2007-09-26. Retrieved 2007-04-12.
- Organon (July 16, 2002). "NuvaRing world's first vaginal birth control ring, first launch now in the US" (PDF). Archived from the original (PDF) on November 30, 2006. Retrieved 2008-09-14.
- "Organon's Once-a-Month Contraceptive Ring, NuvaRing(R) Completes European Authorization". PR Newswire. Retrieved 30 June 2013.