NUVARING: Do Not Use

You have probably seen the ubiquitous ads for NUVARING, a first-of-its kind delivery system of hormonal contraception approved by the Food and Drug Administration (FDA) for pregnancy prevention in 2001.[1],[2] The product, which remains patented until 2018,[3] is the only birth control system on the market that delivers a dose of hormones (estrogen and progestin) through a small ring that is inserted in the vagina each month.

From October 2012 through September 2013, more than 5.2 million prescriptions were filled for NUVARING, making it more popular than any other single brand-name contraceptive product.[4] By contrast, ORTHO-TRI-CYCLEN LO, the next closest competitor, garnered just over 3 million prescriptions (although this figure does not include generic versions).[5] Part of the product’s popularity may be due to the fact that NUVARING remained relatively free from scrutiny through its first decade on the market, a period in which other brand-name contraceptives have been the focus of lawsuits, petitions by consumer groups seeking to ban the products and FDA attention.[6],[7],[8] NUVARING’s manufacturer, Merck, also emphasizes the product’s convenience (used monthly as opposed to daily)[9] and describes it as offering a “continuous low dose of hormones,”[10] suggesting that NUVARING is safer than other hormonal products.

The 2005 edition of the Worst Pills, Best Pills book did not mention NUVARING, because the drug’s sales at the time were relatively low. We are now designating it as Do Not Use, because multiple studies have shown increased risk of blood clotting with drugs from the same family. Some studies have shown increased risk with NUVARING itself, and safer, equally effective forms of contraception are widely available.

Blood-clotting risks

The risk of dangerous blood clots in a normal, healthy woman of reproductive age is very low: Each year, approximately 3 women in 10,000 will experience a blood clot in the veins,[11] 2 women in 10,000 will experience a stroke, and 1 woman in 10,000 will experience a heart attack.[12] The estrogen found in combination hormonal birth control products that also contain a synthetic progesterone (known as a progestin) can easily double or triple the risk of blood clots.[13],[14]

Some progestins are associated with a higher risk of blood-clotting effects than others. For example, numerous studies of third-generation progestins, mainly desogestrel (the progestin found in CYCLESSA, DESOGEN, MIRCETTE, ORTHO-CEPT and many generic products), have found a 1.5- to 2.4-fold higher risk of blood clotting with drugs containing these ingredients compared with older contraceptives containing second-generation oral progestins.[15] Thus, if second-generation progestins result in triple the risk of blood clots relative to not taking hormonal birth control, then desogestrel-containing products would result in an even higher risk. Based on these studies, Public Citizen petitioned the FDA in 2007 to ban products that contain desogestrel.[16]

The progestin found in NUVARING is a slightly different third-generation progestin called etonogestrel.[17] Compared with desogestrel, less information is available on the specific safety risks of etonogestrel. However, desogestrel is known to break down into etonogestrel once inside the body.[18] Because of this relationship, the FDA medical reviewer responsible for evaluating NUVARING prior to its 2001 approval originally recommended adding a stronger warning to the NUVARING safety information highlighting the fact that etonogestrel is a member of a progestin class that carries a higher risk of blood clots.[19]

After negotiating with the drug’s manufacturer (then Organon International), the FDA agreed to a much weaker warning on blood-clotting risk of NUVARING, buried in the fine print of the label.[20],[21] Dr. Susan Allen was the head of the division at the FDA that oversaw the review of birth control products at the time. After NUVARING’s approval, Allen retired from the FDA and was hired as a consultant for Organon.[22]

Studies conducted prior to NUVARING’s approval were not large enough to detect a rare safety risk such as blood clotting. Only one blood clot occurred during clinical testing: A 26-year-old woman developed a blood clot in her leg only eight days after starting NUVARING.[23] Troubling as it was to see such an otherwise rare event develop during clinical testing prior to FDA approval, one blood clot was not enough to draw conclusions about the relative risks of NUVARING compared to other hormonal birth control products.[24]

Since NUVARING came on the market, only a few published studies have provided new data on blood-clotting risk among the product’s users, but these studies were generally not reassuring.

A large observational study conducted in Denmark using hospital discharge data found that NUVARING users were twice as likely to experience blood clots compared with users of second-generation birth control products containing estrogen and levonorgestrel (ALESSE, LOSEASONIQUE, NORDETTE-28, QUARTETTE, SEASONALE, SEASONIQUE and many generic names).[25] These results have been criticized on the grounds that blood-clotting risk is highest among new users, and users of NUVARING in the study were more likely to be just starting out with the product than were the users of older hormonal contraceptives.[26] However, the Denmark study had attempted to adjust for length of use and still found a nearly two-fold increase in risk, though this adjustment may not have been perfect.[27]

An FDA-funded study looking at data from medical insurance claims found a statistically significant 50 percent increase in risk among users of NUVARING compared with users of hormonal contraceptives containing older progestins (levonorgestrel and norethindrone).[28] However, when the researchers narrowed the analysis down to “new users” only (no time frame was specified), they found no increased risk.[29]

Another study compared risk of blood clots with new or returning NUVARING users versus new or returning users of all other combination oral contraceptive pills.[30] That study, funded by NUVARING’s manufacturer (then Organon), found no increased risk of blood clots among NUVARING users.

The NUVARING label avoids presenting the more troubling evidence of increased overall risk among all users, listing only the manufacturer’s study and the FDA’s sub-analysis, both of which focused exclusively on new or returning users.[31],[32],[33] By contrast, the Canadian label for NUVARING includes data from the Denmark study and the full FDA analysis, both of which showed increased risk.[34]

‘Continuous low dose’?

NUVARING continues to be marketed as delivering a “continuous low dose,” suggesting greater safety relative to other hormonal contraceptives, but there is little evidence actually supporting this implication.[35] Surprisingly, this first-of-its-kind product was tested in a small clinical trial involving only 16 human subjects to determine the blood levels of estrogen and progestin achieved with the product.[36] Only data from this trial regarding average blood levels of estrogen and progestin, which were relatively low, appear on the current product label.[37] However, the trial also demonstrated that there was significant variation in estrogen blood levels between subjects and over time for individual subjects. Most shocking of all: Four of the 16 subjects (25 percent) who participated in the small trial experienced an unexplained surge of estrogen, between two and four times the average levels, either at the start of their 30-day menstrual cycles or randomly in the middle of their cycles.

The drug’s original manufacturer, Organon, chose to cover up data from the two patients who experienced mid-cycle surges, neglecting to discuss the surges in a summary report for the trial the company submitted to the FDA in 1999, and omitted the data from the NUVARING professional label. The company explained that concentrations for certain patients were “considered to be ... too high” to include in the analysis. The drug label did include data from the two women who experienced surges at the start of their cycles, but the figure that contained this information was compressed, making it difficult to see the surges clearly.

As of October 2013, the NUVARING label had not been updated to reveal the unexplained mid-cycle surges of estrogen.[38] Unfortunately, correcting the label may do little to assist doctors in prescribing the product safely: Without conducting further large studies to provide better data on relative risk, it is difficult to know what impact these surges actually have on the chance of developing blood clots.

Safer, equally effective birth control options available

The pregnancy rate among women taking NUVARING in clinical trials is about 1 percent, the same effectiveness as other combined estrogen-plus-progestin hormonal contraceptives.[39] Rates of accidental pregnancy are significantly higher among typical real-world users, closer to 9 percent for both NUVARING and oral combination hormonal birth control.[40] Given these comparisons, older combination hormonal contraceptives containing progestins such as levonorgestrel and norethindrone are the better choice, because they have lower risk of blood clotting and the same effectiveness.

The progestin-only pill carries about the same effectiveness as combined estrogen-plus-progestin products (although the various products have not been compared directly in randomized trials).[41] The progestin-only pill also does not increase the risk of blood clotting.[42] However, all progestin-only products carry a greater risk that an accidental pregnancy, if it does occur, will occur outside the uterus. This condition, known as ectopic pregnancy, can result in life-threatening bleeding if left untreated.[43],[44]

Other birth control methods have no serious side effects. A diaphragm or cervical cap, small cups inserted into the vagina to cover the cervix and block sperm, carry no serious side effects and are just slightly less effective in real-world use compared with NUVARING (failure rate of about 12 percent).[45] Other forms of contraception are equally safe but less effective, with real-world failure rates close to 20 percent or higher. These include using male and female condoms (which have the added benefit of protecting against sexually transmitted diseases), withdrawing before ejaculation or having sex only at certain times of the month.[46]

For those seeking longer-term (but not permanent) pregnancy prevention, the progestin-only shot (which lasts three months); progestin-only subdermal, or under the skin, implant (which lasts three years); and two types of intrauterine implants (which last between three and 10 years) are more effective than the pill or NUVARING.[47] These products carry their own safety risks, and many are relatively new to the market, meaning little safety data are available.[48],[49] Like the progestin-only pill, the shot and implant increase the risk that an accidental pregnancy will occur outside the uterus.[50] Intrauterine devices also temporarily increase the risk of pelvic inflammatory disease, and there is a risk that the uterus may become perforated during insertion of the device (particularly if an inexperienced doctor performs the procedure).[51]

What You Can Do

If you are selecting a form of birth control for the first time, do not use NUVARING. Work with your physician to select one of the safer or more effective options listed in this article. The method you choose will depend on your family-planning needs and how you feel about various safety risks involved.

If you are already taking NUVARING, be cautious when switching to another birth control product. If you are taking NUVARING and plan to switch to a nonhormonal or progestin-only method, you can switch right away. However, switching to another form of combined estrogen-plus-progestin product may expose you to additional increased blood-clotting risk. Risk of blood clots among users of combination hormonal contraceptive is higher during the first six months of use and is also elevated after restarting a product after a four-week or greater interval without any treatments.[52] Therefore, if you would like to switch to an older combination hormonal product, it may be safer to wait until a break in NUVARING usage occurs for other reasons (for example, due to a period of sexual inactivity or pregnancy) before switching to the new product.

References

[1] Center for Drug Evaluation and Research. Medical Review for Nuvaring, Part 1. October 6, 2000. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-187_NuvaRing_medr_P1.pdf.

[2] Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist.

[3] Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021187&Product_No=001&table1=OB_Rx.

[4] Brooks M. Top 100 Selling Drugs of 2013. Medscape Multispecialty. January 30, 2014. http://www.medscape.com/viewarticle/820011#2. Accessed February 7, 2014.

[5] Ibid.

[6] Public Citizen. Petition to Ban Third Generation Oral Contraceptives Containing Desogestrel. February 6, 2007. http://www.citizen.org/Page.aspx?pid=532. Accessed February 7, 2014.

[7] Yaz Settlement Alert. http://www.yazlawsuit.com/. Accessed February 7, 2014.

[8] Brooks, M. FDA provides update on drospirenone VTE risk. Medscape. October 27, 2011.

[9] NuvaRing Comparison Results. Merck website. http://www.nuvaring.com/consumer/compare-nuvaring/display-methods.asp?method=1.

[10] NuvaRing website. http://www.nuvaring.com/Consumer/index.asp

[11] Lidegaard O, Lokkegaard E, Louise S, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:b2890. http://www.bmj.com/content/339/bmj.b2890?view=long&pmid=19679613. Accessed February 18, 2014.

[12] Lidegaard O, Lokkegaard E, Jensen A, et al. Thrombotic stroke and myocardial infarction with hormonal contraceptive. N Engl J Med 2012:366;24:2257-2266.

[13] NuvaRing Original Drug Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/21187lbl.pdf

[14] Lidegaard O, Lokkegaard E, Jensen A, et al. Thrombotic stroke and myocardial infarction with hormonal contraceptive. N Engl J Med 2012:366;24:2257-2266.

[15] Public Citizen. Petition to Ban Third Generation Oral Contraceptives Containing Desogestrel. February 6, 2007. http://www.citizen.org/Page.aspx?pid=532. Accessed February 7, 2014.

[16] Ibid.

[17] Sitruk-Ware R. Pharmacological profile of progestins. Maturitas 2004(47):277-283.

[18] Worst Pills, Best Pills, Drug Monograph: desogestrel and ethinyl estradiol. /monographs/view/30. Accessed February 7, 2014.

[19] Center for Drug Evaluation and Research. Medical Review for Nuvaring, Part 1. October 6, 2000. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-187_NuvaRing_medr_P1.pdf

[20] Siddiqui S. Side effects may include death: the story of the biggest advance in birth control since the pill. Huffington Post. December 18, 2013. http://www.huffingtonpost.com/2013/12/18/nuvaring-blood-clots_n_4461429.html. Accessed February 10, 2014.

[21] NuvaRing Original Drug Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/21187lbl.pdf. Accessed February 10, 2014.

[22] Vanity Fair. Why is potentially lethal contraceptive NuvaRing still on the market? December 9, 2013. http://www.vanityfair.com/politics/2014/01/nuvaring-lethal-contraceptive-trial. Accessed February 7, 2014.

[23] Center for Drug Evaluation and Research. Medical Review for Nuvaring, Part 2. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-187_NuvaRing_medr_P2.pdf. Accessed February 11, 2014.

[24] Siddiqui S. Side effects may include death: the story of the biggest advance in birth control since the pill. Huffington Post. December 18, 2013. http://www.huffingtonpost.com/2013/12/18/nuvaring-blood-clots_n_4461429.html. Accessed February 10, 2014.

[25] Lidegaard O, Nielsen LH, Skovlund CW, Lokkegaard E. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10. BMJ 2012;344:e2990.

[26] Roumen FJ, Mishell DR. The contraceptive vaginal ring, NuvaRing, a decade after its introduction. Eur J Contracept Reprod. Health Care. 2012;17:415-427.

[27] Lidegaard O, Nielsen LH, Skovlund CW, Lokkegaard E. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10. BMJ 2012;344:e2990.

[28] Sidney, S (primary author). Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf. Accessed February 10, 2014.

[29] Ibid.

[30] Dinger J, Mohner S, Heinemann K. Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring. Obstet Gynecol 2013;122:800-8.

[31] NuvaRing Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021187s021lbl.pdf. Accessed February 10, 2014.

[32] Sidney, S (primary author). Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf. Accessed February 10, 2014.

[33] NuvaRing Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021187s021lbl.pdf. Accessed February 10, 2014.

[34] NuvaRing Drug Label (Canadian). http://www.merck.ca/assets/en/pdf/products/NuvaRing-PM_E.pdf. Accessed February 11, 2014.

[35] NuvaRing website. http://www.nuvaring.com/Consumer/index.asp.

[36] Food and Drug Administration. Pharmacology Review: NDA 21-187. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-187_NuvaRing_pharmr.pdf

[37] NuvaRing Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021187s021lbl.pdf. Accessed February 10, 2014.

[38] NuvaRing Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021187s021lbl.pdf. Accessed February 7, 2014.

[39] Roumen FJ, Mishell DR. The contraceptive vaginal ring, NuvaRing, a decade after its introduction. Eur. J. Contracept. Reprod. Health Care 2012;17:415-427.

[40] Centers for Disease Control. Effectiveness of Family Planning Methods. http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/PDF/Contraceptive_methods_508.pdf.

[41] Burke A. The state of hormonal contraception today: benefits and risks of hormonal contraceptives: progestin-only contraceptives. Am J Obstet and Gynecol. 2011 Oct;205(4 Suppl):S14-7.

[42] Mantha S, Karp R, Raghavan V, et al. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ 2012;345:e4944.

[43] NexPlanon Drug Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021529s010lbl.pdf

[44] Mayo Clinic. Ectopic Pregnancy: Complications. http://www.mayoclinic.org/diseases-conditions/ectopic-pregnancy/basics/complications/con-20024262.

[45] Centers for Disease Control. Contraception. http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/Contraception.htm.

[46] Centers for Disease Control. Effectiveness of Family Planning Methods. http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/PDF/Contraceptive_methods_508.pdf. Accessed February 11, 2014.

[47] Centers for Disease Control. Contraception. http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/Contraception.htm.

[48] Cornforth T. FDA approves mirana IUD. July 19, 2009. http://womenshealth.about.com/cs/iuds/a/fdaapprvmirena.htm. Accessed February 10, 2014.

[49] Association of Reproductive Health Professionals. The single-rod contraceptive implant. July 2008. http://www.arhp.org/publications-and-resources/clinical-proceedings/Single-Rod/History. Accessed February 10, 2014.

[50] NexPlanon Drug Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021529s010lbl.pdf

[51] Stoddard A, McNicholas C, Peipert JF. Efficacy and safety of long-acting reversible contraception. Drugs 2011;71(8):969-980.

[52] NuvaRing Drug Label (Canadian). http://www.merck.ca/assets/en/pdf/products/NuvaRing-PM_E.pdf. Accessed February 11, 2014.