2

• The contraceptive vaginal ring NuvaRing is a flexible, soft, latex-free device

measuring 54 mm in diameter, and 4 mm in cross-section. It contains 2.7

mg of ethinylestradiol and 11.7 mg of etonogestrel, which is the 3 keto-

metabolite of desogestrel, a third generation progestin.

• The transdermal contraceptive patch is a matrix system measuring 20

square cm, and composed of three layers. The middle layer is medicated

and contains two hormones, 0.60 mg of ethinylestradiol and 6 mg of

norelgestromin, the primary active metabolite of norgestimate, a second

generation progestin.

3

1. Algorta J et al. Pharmacokinetic bioequivalence, safety and acceptability of

Ornibel, a new polymer composition contraceptive vaginal ring

(etonogestrel/ethinylestradiol 11.00/3.474mg) compared with Nuvaring

(etonogestrel/ethinylestradiol 11.7/2.7mg). Europ J Contrac Reprod Health

Care 2017; 22: 429–38.

2. Galzote RM et al. Transdermal delivery of combined hormonal

contraception: a review of the current literature. Int J Womens Health 2017; 9:

315-21.

3. Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone

acetate / Ethinyl estradiol 12-month contraceptive vaginal system safety

evaluation. Contraception 2019 Mar 1. doi:

10.2016/j.contraception.2019.02.001. [Epub ahead of print].

• Since the license for Nuvaring expired in 2017-2018 in most European

countries, several generics of Nuvaring are available at the moment.

• Recently, a new type of vaginal ring became on the market with the same

size and a similar external appearance to Nuvaring, but with a new polymer

composition and containing 3.474 mg of ethinylestradiol and 11.0 mg of

etonogestrel (Ornibel, ExeltisHealthcare, Spain. Algorta et al. EJCRHC

2017;22:429). Ornibel® is bioequivalent to Nuvaring® in terms of efficacy,

safety, tolerability and acceptability. The new polymer composition provides

Ornibel® with more stability making storage in the refrigerator unnecessary,

and a more gradual hormonal release during the first day of use,

4

particularly for ethinylestradiol.

• Also contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or

500-900 µg/day of NOMAC are in development (Duijkers et al. EJCRHC

2018;23:245).

• The one-year reusable segesterone acetate (Nestorone) and ethinyl

estradiol (SA/EE) latex-free ring Annovera is 56 mm in overall diameter and

8.4 mm in cross-sectional diameter. The ring is worn for three weeks and

removed for one week, and that pattern is repeated for a total of 13 cycles.

The device releases approximately 150 mcg/day of SA and 13 mcg/day of

EE over the 21-day use period. Other product advantages include that it

does not require refrigeration for storage and that it is not orally active,

which may appeal to lactating women. Annovera was approved by the U.S.

Food and Drug Administration (FDA) in August 2018. The product is

anticipated to be available in 2019.

• Two new patches with lower estrogen exposure based on AUC and

different progestins (gestodene or levonorgestrel) are under investigation.

One is a smaller, transparent EE/GSD patch being studied in Europe (11

cm2 patch containing 0.55 mg EE-2.1 mg GSD).

The other is the EE/LNG patch in the US that has not yet received FDA

approval (15 cm2 patch containing 2.3 mg EE-2.6 mg LNG).

• Two novel LNG-only patches (40 mcg or 75 mcg daily) did not decrease

pregnancy risk adequately (Westhoff 2018).

4

• After pressing the sides together, the ring is inserted into the vagina as high

as possible, where it sits above the urogenital diaphragm and surrounds

the cervix, although the position of the ring does not affect contraceptive

efficacy. The ring can easily be removed by hooking a finger in it.

• The patch is applied to clean, dry, intact healthy skin of the buttock,

abdomen, upper torso or upper outer arm, but not to the breast, as it might

cause breast tenderness due to high local estrogen concentration. A

different site is used each time a new patch is applied. Lotions and

occlusive dressings should not be used at patch application sites.

5

1.Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and

ethinylestradiol released from a combined contraceptive vaginal ring. Clin

Pharmacokinet 2000; 39:233.

2. van den Heuvel M W, van Bragt AJM, Alnabawy AKM, Kaptein MCJ.

Comparison of ethinylestradiol pharmacokinetics in three hormonal

contraceptive formulations: The vaginal ring, the transdermal patch and an

oral contraceptive. Contraception 2005; 72:168.

3.Ortho Evra (norelgestromin/ethinyl estradiol transdermal system). Product

labeling. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc, Revised September

2006.

4. Devineni D, Skee D, Vaccaro N, et al. Pharmacokinetics and

pharmacodynamics of a transdermal contraceptive patch and an oral

contraceptive. J Clin Pharmacol 2007; 47:497.

• The ring releases 15 µg EE and 120 µg ENG daily, and the patch 35 µg of

EE and 200 µg of norelgestromin.

• As a result, and calculated in this randomized study, systemic exposure to

EE with the vaginal ring is 3.4 times lower than with the patch, and 2.1

times lower than with a 30 µg pill, whereas the overall EE concentration in

patch users is comparable to that of a 50 µg EE pill.

6

1.Mulders TM, Dieben TO. Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition. Fertil Steril 2001; 75:865.2. Killick S. Complete and robust ovulation inhibition with NuvaRing. Eur J Contracept Reprod Health Care 2002; 7 Suppl 2:13.3.Barnhart KT, Timbers K, Pretorius ES, et al. In vivo assessment of NuvaRing® placement. Contraception 2005; 72:1964.Miller L, Verhoeven CH, Hout Ji. Extended regimens of the contraceptive vaginal ring: a randomized trial. Obstet Gynecol 2005; 106:473.5.Barreiros FA, Guazzelli CA, de Araújo FF, et al. Bleeding patterns of women using extended regimensof the contraceptive vaginal ring. Contraception 2007; 75:204.6.Guazzelli CA, Barreiros FA, Barbosa R, et al. Extended regimens of the vaginal contraceptive ring: cycle control. Contraception 2009; 80:430.7.Dragoman M, Petrie K, Torgal A, et al. Contraceptive vaginal ring effectiveness is maintained during 6 weeks of use: a prospective study of normal BMI and obese women. Contraception 2013; 87:432.8.Stewart FH, Kaunitz AM, Laguardia KD, et al. Extended use of transdermal norelgestromin/ethinylestradiol: a randomized trial. Obstet Gynecol 2005; 105:1389.9. Lopez LM, Newmann SJ, Grimes DA, et al. Immediate start of hormonal contraceptives for contraception. Cochrane Database Syst Rev 2012; 12:CD006260.10.Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep 2016; 65:1.

Use of the CVR and the CTPThe ring and the patch should be initiated within five days after the start of the menstrual bleeding. Each ring remains in the vagina for three weeks, and is then removed for one week. The patch is changed once a week for three weeks, followed by one patch-free week. The patch should always be changed on the same day of the week, which is known as the ‘Patch change day’. If a woman wants to switch to a new patch change day, she has to do that in the patch-free week.

Women who desire fewer days of withdrawal bleeding and are willing to tolerate some unscheduled bleeding, can safely use an extended ring regimen for up to one year, whereby the ring is changed every three weeks. Omitting the hormone-free week is also possible for the patch, but we advise to avoid this practice, given the possible incremental EE serum levels when patches are used continuously, resulting in increased risk of side effects such as headache, nausea, breast discomfort and thrombosis.

7

1. Mulders TM, Dieben TO. Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition. Fertil Steril 2001; 75:865.2. Mulders TM, Dieben TO, Bennink HJ. Ovarian function with a novel combined contraceptive vaginal ring. Hum Reprod 2002; 17:2594.3. Killick S. Complete and robust ovulation inhibition with NuvaRing. Eur J Contracept Reprod Health Care 2002; 7 Suppl 2:13.4. Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 2002; 100:585.5. Duijkers IJ, Klipping C, Verhoeven CH, Dieben TO. Ovarian function with the contraceptive vaginal ring or an oral contraceptive: a randomized study. Hum Reprod 2004; 19:2668.WHO. Selected practice recommendations for contraceptive use • Third edition 2016

There are quite a number of similarities between the ring, the patch and the pill. • The three methods have a similar systemic contraceptive working mechanism,

such as inhibition of ovulation, thickening of the cervical mucus, decreasing of endometrial receptivity, and slowing of tubal motility.

• The WHO medical eligibility criteria for initiating and use are the same, in particular the postpartum use in breastfeeding and non-breastfeeding women.

• Effectiveness is similar, as are the general non-contraceptive benefits, risks and general contraindications, and the absence of clinically significant metabolic effects, such as changes in blood pressure, blood chemistries, lipid levels, carbohydrate metabolism, thyroid function, and hematological indices.

• Initiation, switching and need for a back-up method in case of extension of the hormone-free interval, or unscheduled non-use, are also essentially the same, and return of ovulation is equally rapid after stopping.

• Also follow-up rules are the same: in healthy women, no examinations or tests are essential or mandatory.

8

The ring and the patch offer several potential advantages to the pill:

• There is no enzymatic degradation in the gastrointestinal tract and no first-

pass hepatic metabolism, resulting in lower doses to achieve therapeutic

effects.

• Plasma hormone levels remain constant: there are no daily peaks and

troughs.

• There is no need for daily self-administration, which might improve user

compliance.

• The non-oral route of administration is useful for patients who have

difficulty swallowing pills.

9

1. Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 2002; 100:585.2. Trussell J. Contraceptive failure in the United States. Contraception 2011; 83:397.3. Lopez LM, Grimes DA, Gallo MF, et al. Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev 2013; :CD003552.4. Hedon, B, Helmerhorst, FM, Cronje, HS, Shangold, G, et al. Comparison of efficacy, cycle control, compliance, and safety in users of a contraceptive patch versus an oral contraceptive. BJOG 2000; 70:78.5. Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA 2001; 285:2347. 6. Smallwood GH, Meador ML, Lenihan JP, et al. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol 2001; 98:799.7. Archer DF, Bigrigg A, Smallwood GH, et al. Assessment of compliance with a weekly contraceptive patch (Ortho Evra/Evra) among North American women. FertilSteril 2002;77:S27.8. Zieman M, Guillebaud J, Weisberg E, et al. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002 ; 77:S13.9. Urdl W, Apter D, Alperstein A, et al. Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared withoral contraception. Eur J Obstet Gynecol Reprod Biol 2005; 121: 202.10. Lopez LM, Bernholc A, Chen M et al. Hormonal contraceptives for contraception in overweight or obese women. Cochrane Database Syst Rev 2016;(8):CD008452. 11. Simmons KB, Edelman AB. Hormonal contraception and obesity. Fertil Steril2016;106:1282-8. 12. Dragoman MV, Simmons KB, Paulen ME et al. Combined hormonal contraceptive (CHC) use among obese women and contraceptive effectiveness: a systematic review Contraception 2017;95:117–29.

The pregnancy rate of the ring and the patch during the first year of use is equivalent

10

to that of the pill: 9% for typical use, and 0.3% for correct use.

However, phase III data suggest, that the patch may be less effective in

women with body weight ≥90 kg. So the patch should preferably not be

prescribed to obese women.

10

1. WHO. Selected practice recommendations for contraceptive use • Third

edition 2016

• The principles of dosing errors with the ring and patch are similar to those

of pill use.

• In case of extension of the ring- or patch-free week, or in case of

unscheduled removal of the ring or detachment of the patch, a new ring or

patch should be applied as soon as possible, and the woman should keep

to the originally scheduled ring removal or patch change day.

• If this occurs within 48 h, no additional contraception is needed.

• If the interval is extended for more than 48 h, the woman should also use

condoms or abstain from sex until she has used a ring or patch for 7 days

in a row.

• If unprotected sexual intercourse occurred during the previous 5 days in the

hormone-free interval, or on any day during the first week, the woman may

wish to consider using EC.

• If sexual intercourse occurred during the third week, the woman should

omit the ring- or patch-free week, and start a new ring or patch

immediately.

11

1. Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinet 2000; 39:233.2. Dragoman M, Petrie K, Torgal A, et al. Contraceptive vaginal ring effectiveness is maintained during 6 weeks of use: a prospective study of normal BMI and obese women. Contraception 2013 ;87:432.3.WHO. Selected practice recommendations for contraceptive use • Third edition 20164. Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep 2016; 65:1.

The rules for extended use of the ring and the patch are quite different.RING: If a woman forgets to remove the ring after three weeks, inhibition of ovulation is sufficiently maintained for another 2 weeks. So, if the same ring is used for up to 28 days, additional contraception is not needed. A hormone-free interval can be taken, if desired, but should not exceed 7 days. If the same ring is used for 28-35 days, insert a new ring and skip the hormone-free interval. In this situation no additional contraceptive protection is needed.Patch: If a woman forgets to change the patch after one week, there is only a two-day period of adequate contraceptive steroid levels. If users change the second or third patch within this window, there is no need for back-up contraception. After these two days, users will need back-up contraception or avoid sex for seven days and, in some instances, use emergency contraception. In all cases, the woman should keep the same patch change day.

12

1. Haring T, Mulders TMT. The combined contraceptive ring NuvaRing® and spermicide co-medication. Contraception 2003; 67:271.2. Verhoeven CHJ, Dieben TOM. The combined contraceptive vaginal ring, NuvaRing®, and tampon co-usage. Contraception 2004; 69:197.3. Dogterom P, van den Heuvel MW, Thomsen T. Absence of pharmacokinetic interactions of the combined contraceptive vaginal ring NuvaRing with oral amoxicillin or doxycycline in two randomised trials. Clin Pharmacokinet 2005; 44:429.4. Verhoeven CHJ, van den Heuvel MW, Mulders TMT, et al. The contraceptive vaginal ring, NuvaRing®, and antimycotic co-medication. Contraception 2004; 69:129.5. Abrams, LS, Skee, D, Natarajan, J, et al. Tetracycline HCL does not affect the pharmacokinetics of a contraceptive patch. Int J Gynecol Obstet 2000; 70:57.6. Schurmans C, De Baetselier I, Kestelyn E, et al. BMC Public Health 2015; 15: 348.

• In ring users, serum EE and ENG levels are not altered by concurrent use of a spermicide (nonoxynol-9), nor by use of tampons. Also, concurrent use of antibiotics (amoxicillin and doxycyclin) does not alter these serum levels. On the contrary, concomitant vaginal use of the antifungal miconazole, has been shown to increase release of both steroids.

• In patch users, serum levels of EE and norelgestromin are not affected by concurrent use of tetracycline. However, it remains possible that efficacy of the patch may be affected by some other drugs.

• Research (Ring Plus Project) is ongoing to develop multipurpose vaginal

13

rings to be used continuously for contraception and to prevent HIV infection

(dapivirine-containing vaginal ring).

13

1.Roumen FJ, Apter D, Mulders TM, Dieben TO. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol. Hum Reprod 2001; 16:469.2.Bjarnadóttir RI, Tuppurainen M, Killick SR. Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol. Am J Obstet Gynecol 2002; 186:389.3.Veres S, Miller L, Burington B. A comparison between the vaginal ring and oral contraceptives. Obstet Gynecol2004; 104:555.4.Westhoff C, Osborne LM, Schafer JE, Morroni C. Bleeding patterns after immediate initiation of an oral comparedwith a vaginal hormonal contraceptive. Obstet Gynecol 2005; 106:89.5.Oddsson K, Leifels-Fischer B, Wiel-Masson D, et al. Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial. Hum Reprod 2005; 20:557.6. Milsom I, Lete I, Bjertnaes A, et al. Effects on cycle control and bodyweight of the combined contraceptive ring, NuvaRing, versus an oral contraceptive containing 30 microg ethinyl estradiol and 3 mg drospirenone. Hum Reprod2006; 21:2304.7. Sabatini R, Cagiano R. Comparison profiles of cycle control, side effects and sexual satisfaction of three hormonal contraceptives. Contraception 2006; 74:220.8. Merki-Feld GS, Hund M. Clinical experience with NuvaRing in daily practice in Switzerland: cycle control and acceptability among women of all reproductive ages. Eur J Contracept Reprod Health Care 2007; 12:240.9. Sandhya J, Vaid NB, Narang Y, et al. A randomised controlled trial comparing the efficacy and side-effects of intravaginal ring (Nuvaring®) with combined oral hormonal preparation in dysfunctional uterine bleeding. J Clin DiagnRes 2016;10:QC21-4.10. Fan GS, Ren M, Di W, et al. Efficacy and safety of the contraceptive vaginal ring (Nuvaring) compared with a combined oral contraceptive in Chinese women: a 1-year randomised trial. Europ J Contrac Reprod Health Care 2016;21:303.11. Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermalcontraceptive patch vs an oralcontraceptive: a randomized controlled trial. JAMA 2001;285:2347–54.12. Burkman RT. Transdermal hormonal contraception: benefits and risks. Am J Obstet Gynecol 2007; 197:134.e1.13. Urdl W, Apter D, Alperstein A, et al. Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Biol2005; 121: 202. 14.Lopez LM, Grimes DA, Gallo MF, et al. Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev 2013; :CD003552.15. Fan GS, Ren M, Di W. Efficacy and safety of the contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive in Chinese women: a 1-year randomised trial. Eur J Contracept Reprod Health Care 2016; 21: 303.16. Dahiya P, Dalal M, Yadav A, et al. Efficacy of combined hormonal vaginal ring in comparison to combined hormonal pills in heavy menstrual bleeding. Eur J Obstet Gynecol Reprod Biol 2016; 203: 147.

• As we all know, cycle control is a benefit of all combined hormonal contraceptive methods. • In several randomised contolled trials, it has been shown, that in ring users, cycle control is at least equivalent or

even superior to that of the pill and the patch. Ring users are less likely than pill users to experience spotting and breakthrough bleeding, especially in the first few months of use. Also less likely among ring users are prolonged or frequent bleeding, and early or late withdrawal bleeding.

14

• An improvement in cycle control has also been demonstrated among

women who switch from the pill or the patch to the vaginal ring, and in

women with dysfunctional uterine bleeding.

• In patch users, unscheduled bleeding is a common side effect in the first

two cycles of use. The pattern of breakthrough bleeding and spotting with

the patch is similar to that reported in pill trials. By about six months, the

frequency of such bleeding declines substantially and remains stable.

14

1. Roumen FJ, Apter D, Mulders TM, Dieben TO. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol. Hum Reprod 2001; 16:469.2. Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 2002; 100:585.3. Bjarnadóttir RI, Tuppurainen M, Killick SR. Comparison of cycle control with a combinedcontraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol. Am J Obstet Gynecol 2002; 186:389.4. Guida M, Di Spiezio Sardo A, Bramante S, et al. Effects of two types of hormonal contraception--oral versus intravaginal--on the sexual life of women and their partners. Hum Reprod 2005; 20:1100.5. Ahrendt HJ, Nisand I, Bastianelli C, et al. Efficacy, acceptability and tolerability of the combined contraceptive ring, NuvaRing, compared with an oral contraceptive containing 30 microg of ethinylestradiol and 3 mg of drospirenone. Contraception 2006; 74:451.6. Roumen FJ, op ten Berg MM, Hoomans EH. The combined contraceptive vaginal ring (NuvaRing): first experience in daily clinical practice in The Netherlands. Eur J Contracept Reprod Health Care 2006; 11:14.7. Schafer JE, Osborne LM, Davis AR, Westhoff C. Acceptability and satisfaction using Quick Start with the contraceptive vaginal ring versus an oral contraceptive. Contraception 2006; 73:488.8. Sabatini R, Cagiano R. Comparison profiles of cycle control, side effects and sexual satisfaction of three hormonal contraceptives. Contraception 2006; 74:220.9. Merki-Feld GS, Hund M. Clinical experience with NuvaRing in daily practice in Switzerland: cycle control and acceptability among women of all reproductive ages. Eur J Contracept Reprod Health Care 2007; 12:240.10.Urdl W, Apter D, Alperstein A, et al. Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet GynecolReprod Biol 2005; 121: 202.11. Lopez LM, Grimes DA, Gallo MF, et al. Skin patch and vaginal ring versus combined oralcontraceptives for contraception. Cochrane Database Syst Rev 2013; :CD003552.12. Kestelyn E, Ilo Van Nuil J, Umulisa MM, et al. High acceptability of a contraceptive vaginal ring among women in Kigali, Rwanda. PLOS ONE | https://doi.org/10.1371/journal.pone.0199096 June 18, 2018.

• Vaginal ring users are either as satisfied or more satisfied than pill users. 84% to 96% of ring users report being satisfied, as they find that the vaginal ring is easy to use, requires only once-a-month administration, remains effective if removal and reinsertion is not performed precisely on time, results in low systemic hormone levels, and is rapidly effective and reversible.

• Several randomized trials have reported improved psychological and sexual functioning among ring users as compared with pill users, but -in contrast- one randomized trial found that ring users reported more decreased libido compared to users of a levonorgestrel-containing pill (8.3 versus 0 percent).

• Only one patch RCT had satisfaction data, showing that patch users were more likely to be very

15

satisfied with their method than pill users.

15

1. Roumen FJ, Apter D, Mulders TM, Dieben TO. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol. Hum Reprod 2001; 16:469.2. Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 2002; 100:585.3. Oddsson K, Leifels-Fischer B, Wiel-Masson D, et al. Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: arandomized trial. Hum Reprod 2005; 20:557.4. Ahrendt HJ, Nisand I, Bastianelli C, et al. Efficacy, acceptability and tolerability of the combined contraceptive ring, NuvaRing, compared with an oral contraceptive containing 30 microg of ethinyl estradiol and 3 mg of drospirenone. Contraception 2006; 74:451.5. Merki-Feld GS, Hund M. Clinical experience with NuvaRing in daily practice in Switzerland: cycle control and acceptability among women of all reproductive ages. Eur J Contracept Reprod Health Care 2007; 12:240.6. Gilliam ML, Neustadt A, Kozloski M, et al. Adherence and acceptability of the contraceptive ring compared with the pill among students: a randomized controlled trial. Obstet Gynecol 2010; 115:503.7. Bitzer J, Gemzell-Danielsson K, Roumen F, et al. The CHOICE study: Effect of counselling on the selection of combined hormonal contraceptive methods in 11 countries. Eur J Contracept Reprod Health Care 2012; 17:65-78.8. Stuart JE, Secura GM, Zhao Q, et al. Factors associated with 12-month discontinuation among contraceptive pill, patch, and ring users. Obstet Gynecol 2013; 121:330.9. Urdl W, Apter D, Alperstein A, et al. Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Biol 2005; 121: 202.10.Kluft C, Meijer P, LaGuardia KD, et al. Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables. Contraception 2008; 77: 77.11. Lopez LM, Grimes DA, Gallo MF, et al. Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev 2013; :CD003552.

• Adherence with the vaginal ring regimen varies between different studies from 80 to 90% of cycles. Discontinuation of the ring occurs in 28 to 35% of women before one year, with most discontinuations occurring in the first three to four cycles. However, side effects were reported as reason for discontinuation in only 11 to 30 % of the ring users.

• RCTs examining the continuation rate report different results. While one RCT found that ring users overall were less likely to discontinue than pill users (12 versus 22 %), another RCT observed no difference. A RCT trial including 201 women using the “quick start” method, found, that ring users were less likely to discontinue than OC users (11% versus 16%).

• Adherence to the patch dosing regimen was shown to be superior to that for pills, in two adequate and well-controlled comparative trials (89% vs. 79%, respectively). However, discontinuation rates, and side effects as reason for discontinuation, were higher for patch users than for pill users.

16

1. O'Connell KJ, Osborne LM, Westhoff C. Measured and reported weight change for women using a vaginal contraceptive ring vs. a low-dose oral contraceptive. Contraception 2005; 72:323.2. Ahrendt HJ, Nisand I, Bastianelli C, et al. Efficacy, acceptability and tolerability of the combined contraceptive ring, NuvaRing, compared with an oral contraceptive containing 30 microg of ethinylestradiol and 3 mg of drospirenone. Contraception 2006; 74:451.3. Schafer JE, Osborne LM, Davis AR, Westhoff C. Acceptability and satisfaction using Quick Start with the contraceptive vaginal ring versus an oral contraceptive. Contraception 2006; 73:488.4. Sabatini R, Cagiano R. Comparison profiles of cycle control, side effects and sexual satisfaction of three hormonal contraceptives. Contraception 2006; 74:220.5.Milsom I, Lete I, Bjertnaes A, et al. Effects on cycle control and bodyweight of the combined contraceptive ring, NuvaRing, versus an oral contraceptive containing 30 microg ethinyl estradiol and 3 mg drospirenone. Hum Reprod 2006; 21:2304.6.Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA 2001; 285: 23477. Sibai BM, Odlind V, Meador ML, et al. A comparative and pooled analysis of the safety and tolerability of the contraceptive patch (Ortho Evra/Evra). Fertil Steril 2002; 77:S19.8. Urdl W, Apter D, Alperstein A, et al. Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Biol 2005; 121: 202. 9.Lopez LM, Grimes DA, Gallo MF, et al. Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev 2013; :CD003552.

• Systemic side effects from the vaginal ring and the patch are generally similar to those of oral contraceptives.

• However, estrogen-related side effects like breast tenderness and nausea, and also acne, are reported less often by vaginal ring users than pill users, a finding that is consistent across three trials comparing the ring with pills of varying ethinyl estradiol doses and different progestins.

• For trials comparing the patch to a pill, more breast symptoms during the first two cycles were reported, more nausea and vomiting, and more dysmenorrhea. About 85% of women experiencing breast symptoms described them as mild to moderate; the frequency declined markedly with continued use of the method. In one study, patch users reported less moodiness than pill users.

• No differences in headache or weight gain were seen across studies comparing ring users to pill users, or patch users to pill users.

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1. Timmer C J, Mulders T MT. Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinet 2000; 39:233.2. Roumen FJME, Apter D , Mulders TMT, Dieben TOM. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyloestradiol. Hum Reprod 2001; 16:469.3. Dieben T OM, Roumen F JME, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 2002; 100:585.4. Veres S, Miller L, Burington B. A comparison between the vaginal ring and oral contraceptives. Obstet Gynecol2004; 104:555.5. Ahrendt HJ, Nisand I, Bastianelli C, et al. Efficacy, acceptability and tolerability of the combined contraceptive ring, NuvaRing, compared with an oral contraceptive containing 30 microg of ethinyl estradiol and 3 mg of drospirenone. Contraception 2006; 74:451.6. Sabatini R, Cagiano R. Comparison profiles of cycle control, side effects and sexual satisfaction of three hormonal contraceptives. Contraception 2006; 74:220.7. Roumen FJME, op ten Berg MMT, Hoomans EHM. The combined contraceptive vaginal ring (NuvaRing®): First experience in daily clinical practice in The Netherlands. Eur J Contracept Reprod Health Care 2006; 11:14.8. Merki-Feld GS, Gruber IM. Intention to use a combined contraceptive method and choice after structured counseling in Switzerland. Eur J Contracept Reprod Health Care 2012; 17: 119.9. Creinin MD, Meyn LA, Borgatta L, et al. Multicenter comparison of the contraceptive ring and patch: A randomized controlled trial. Obstet Gynecol 2008; 111:267.10. Brucker C , Karck U , Merkle E. Cycle control, tolerability, efficacy and acceptability of the vaginal contraceptive ring, NuvaRing®: Results of clinical experience in Germany. Eur J Contracept Reprod Health Care 2008; 13:31.11.Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA 2001; 285: 234712. Zacur HA, Hedon B, Mansour D, et al. Integrated summary of Ortho Evra/Evra contraceptive patch adhesion in varied climates and conditions. Fertil Steril 2002; 77:S32.13. Urdl W, Apter D, Alperstein A, et al. Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Biol 2005; 121: 202.14. Kestelyn E, Agaba S, Ilo Van Nuil J, et al. A randomised trial of a contraceptive vaginal ring in women at risk of HIV infection in Rwanda: Safety of intermittent and continuous use. PLOS ONE | https://doi.org/10.1371/journal.pone.0199096 June 18, 2018.15. Crucitti T, Hardy L, van de Wijgert J, et al. Contraceptive rings promote vaginal lactobacilli in a high bacterialvaginosis prevalence population: A randomised, open-label longitudinal study in Rwandan women. PLOS ONE | https://doi.org/10.1371/journal.pone.0201003 July 23, 2018.

• Problems related to the ring and patch methods are important.• Ring users report more local vaginal symptoms such as vaginitis, vaginal wetness, and vaginal discharge (17%)

than pill users. These symptoms, however, do not require treatment and do not appear to result in discontinuation of the ring. Use of the ring is not associated with a higher likelihood of bacterial vaginosis.

• In the large European efficacy study, device related events including foreign body sensation, coital problems and expulsion was reported by 4.1% of women. In the large comparative studies in Europe these percentages were 4.7% and 6.6%. In a Swiss daily practice study, 1,7% of women reported expulsion of the ring and in a Dutch daily practice study

18

6%. In this study, a statistically significant negative linear relation was

demonstrated between ease of insertion and expulsion. These European

percentages are much lower than those reported in the USA and Africa. In

a USA ring-pill cross-over study, 9% reported ring slippage at least once

weekly. In the randomised controlled trial in the USA comparing the CVR

and the patch, the ring was expelled at least once during any three-week

period in 20.4% of women. Participants in the RCT in Rwanda reported

spontaneous expulsions in 14% of the ring use periods.

The higher figures in the US and Africa may be related to differences in

populations, cultures, way of instruction, ease of insertion, sexual practices

(e.g. removal CVR during sex), toilet positions, etc., but also to differences

in definition (frequency, partial or complete expulsion, voluntary removal or

spontaneous loss, etc.).

So, ring expulsion may occur spontaneously, and women should be

counselled to check for the presence of the ring after coitus, a strenuous

effort (e.g., at defaecation), or tampon removal. If the ring accidentally falls

out, it may be rinsed with cool or warm water, and reinserted into the

vagina within three hours.

• Studies show that from 13-16% of users chose to remove the ring during

intercourse. This interval of removal does not affect efficacy if the ring is

reinserted within a three-hour time interval.

• In patch users, mild-to-moderate application site reactions were reported

by 14-20% of women, and 2,6% of them stopped treatment for this reason.

The patch adhered well with only 4.7% of all patches being replaced due to

complete or partial detachment. Neither living in a warm, humid climate nor

having a vigorous, athletic lifestyle increases the risk of detachment.

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1. Creinin MD, Meyn LA, Borgatta L, et al. Multicenter comparison of the contraceptive ring and patch. A Randomized Controlled Trial. Obstet Gynecol 2008; 111: 267

• The acceptability of the ring and the patch were compared in a RCT during four consecutive cycles.

• The percentage of women who completed three cycles was significantly higher for ring users in the per protocol population, and in the intent-to-treat population as well.

• The most common reasons cited for ring discontinuation were discomfort with use and adverse effects. For patch discontinuation, reasons cited were adverse effects, skin irritation and problems with adherence.

• Of the women who completed three cycles, significantly more ring users planned to continue use of their method.

• Ring users were significantly more likely than patch users to experience frequent vaginal discharge, and that the device was bothersome during sex to them or their partners, whereas patch users were significantly more likely to experience longer periods, increased dysmenorrhea, frequent nausea, frequent mood swings, and frequent skin rash.

• Device-related problems were noted at least once during any 3-week use period more frequently with the patch: the patch fell off in 46.0% of women and the ring was expelled in 20.4% of women.

• As a result, significantly more women stated they were satisfied with the ring than with the patch.

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1. Lidegaard Ø, Nielsen LH, Skovlund CW, Løkkegaard E. Venous trombosis

in users of non-oral hormonal contraception: follow-up study, Denmark 2001-

10. BMJ 2012;344:e2990.

2. Lidegaard Ø, Løkkegaard E, Jensen A, et al. Thrombotic stroke and

myocardial infarction with hormonal contraception. N Engl J Med 2012;

366:2257.

3. Sidney S, Cheetham CT, Connell FA, et al. Recent combined hormonal

contraceptives (CHCs) and the risk of thromboembolism and other

cardiovascular events in new users. Contraception 2013;87:93-100.

4. Dinger J, Möhner S, Heinemann K. Cardiovascular risk associated with the

use of an etonogestrel-containing vaginal ring. Obstet Gynecol 2013; 122:800.

5.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/

general_content_000581.jsp&mid=WC0b01ac05806b6b24

6. Tepper NK, Dragoman MV, Gaffield ME, et al. Nonoral combined hormonal

contraceptives and thromboembolism: a systematic review. Contraception

2017;95:130-139.

7. O'Brien SH, Koch T, Vesely SK, Schwarz EB. Hormonal Contraception and

Risk of Thromboembolism in Women With Diabetes. Diabetes Care 2017;

40:233.

According to the EMAS statement 2013, the risk of VTE for the ring containing

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etonogestrel and the patch containing norelgestromin, is 6-12 per 10,000

women over a year, which is twofold the risk of a second generation pill.

In particular, diabetic women appear to be at increased risk of VTE with patch

use. In a database study of over 36,000 women with either type 1 or 2

diabetes who were continuously prescribed contraceptives, the VTE rate for

users of estrogen-progestin oral pills, vaginal rings, and patches, after

controlling for other potential risk factors, was 10.3, 13.5, and 16.4 per 1000

women, respectively. The increased VTE risk has been attributed to the

observation that the average overall ethinyl estradiol (EE) concentration

("area under the curve") in patch users is 60 percent higher than in women

who use a 35-mcg EE pill.

20

1.Dinger J, Mohner S, Heinemann K. Cardiovascular risk associated with the

use of an etonogestrel-containing vaginal ring. Obstet Gynecol 2013; 122:

800.

2.Dore DD, Norman H, Loughlin J, et al. Extended case–control study results

on thromboembolic outcomes among transdermal contraceptive users.

Contraception 2010; 81: 408.

3.Jick SS, Hagberg KW, Hernandez RK, et al. Postmarketing study of

ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal

contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous

thromboembolism. Contraception 2010; 81: 16.

4.Tepper NK, Dragoman MV, Gaffield ME, et al. Nonoral combined hormonal

contraceptives and thromboembolism: a systematic review. Contraception

2017;95:130-139.

• A systematic review of primary research studies did not demonstrate an

increased risk of arterial thromboembolism among women using the ring.

Results from one prospective study revealed no significant difference as

compared to a reference group of women using multiple types of pills.

• Two studies compared patch users to NGM pill users, and neither found a

statistically significant difference in AMI or ischemic stroke.

21

1. Gupta N, Corrado S, Goldstein M. Hormonal contraception for the

adolescent. Pediatr Rev 2008; 29:386.

2. Lavelanet AF, Rybin D, White KO. The pharmacokinetics of 12-week

continuous contraceptive patch use. Contraception 2017;95:578–585.

• Candidates for the vaginal ring and the patch are women who desire highly

effective, reversible, non-coitally-dependent contraception, who have no

contraindications to taking estrogen or progestins. Also, women who do not

want a pill, or who have gastrointestinal problems, or who forget to swallow

a pill daily, are good candidates. For example, adolescents with their

irregular lives.

• The ring is contraindicated in women with complaints of a pelvic organ

prolapsed, or a genital touch taboo, the patch in women with dermatologic

problems, overweight or diabetes.

• In contrast to the patch, use of the ring may be advisable for women who

want a lower estrogen exposure to the body, who want a better cycle

control than experienced during pill use, or who want to use an extended

regimen. Extended use of the patch is associated with an accumulation of

EE2 and possible associated adverse events.

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