Topic CHC IV: CVR-CTP Combined hormonal contraceptives CHC Session IV Vaginal Ring CVR – Transdermal Patch CTP Advanced slide kit complementing the WHO training tool www.fptraining.org Update March 2019
Advanced slide kit complementing the WHO training tool www.fptraining.org
Update March 2019
Topic CHC IV: CVR-CTP
Contents
• Description and formulation; Application• Pharmacokinetics; Regimen of use• Similarities ring, patch and pill; Advantages ring and patch > pill• Contraceptive failure rates• Dosing errors; Extended use• Concurrent use• Cycle control; Acceptability; Compliance; Side effects compared with
pill• Device-related problems; Acceptability ring vs patch• Venous and arterial thromboembolism• Counselling
To enable teachers to understand and explain:
Topic CHC IV: CVR-CTP
Description and formulationVaginal ring
• Flexible, soft, latex-free ring, 54 mm in diameter, 4 mm in cross-section
• Contains 2.7 mg EE and 11.7 mg ENG
Transdermal patch• Matrix system, 20 cm2,
3 layers• Middle layer contains
0.60 mg EE and 6 mg NGMN (EU)
Ref 1, 2
Vorführender
Präsentationsnotizen
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.
Topic CHC IV: CVR-CTP
Alternatives (or in development)Vaginal ring
• Generics of Nuvaring• Ornibel (EE/ENG)• E2/ENG rings• E2/NOMAC rings• SA/EE ring (Annovera)
Transdermal patch• EE/GSD patch• EE/LNG patch• LNG only patch
Ref 1-3
Vorführender
Präsentationsnotizen
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, 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).
Topic CHC IV: CVR-CTP
ApplicationVaginal ring Transdermal patch
• Clean, dry, intact healthy skin
• Not on the breast• Each time different site• No lotions or occlusive
dressings
Vorführender
Präsentationsnotizen
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.
Topic CHC IV: CVR-CTP
PharmacokineticsVaginal ring
• Daily release 15 µg EE and 120 µg ENG
• Systemic EE exposure low(3.4x lower than patch) (2.1x lower than 30 mcg pill)
Transdermal patch• Daily release 35 µg EE and
200 µg NGMN• Overall EE concentration ≈ 50
mcg EE pill
Ref 1-4, Graph Ref 2
Vorführender
Präsentationsnotizen
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.
Topic CHC IV: CVR-CTP
Regimen of useVaginal ring
• Start cycle day 1-5• 3 weeks in, 1 week out
• Omitting hormone-freeweek possible
• Extended use: unscheduled bleeding
Transdermal patch• Start cycle day 1-5• Once a week for 3
weeks, 1 week out• Switch of patch change
day in patch-free week• Omitting hormone-free
week not advised• Extended use:
headache, nausea, mastodynia, thrombosis
Ref 1-10
Vorführender
Präsentationsnotizen
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; 72:196 4.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 regimens of 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/ethinyl estradiol: 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 CTP The 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.
Topic CHC IV: CVR-CTP
Similarities: ring, patch and pill• Combined hormonal method• Systemic working mechanism• Medical eligibility criteria (WHO)• Postpartum use (breastfeeding and non-breastfeeding)• Effectiveness• Non-contraceptive benefits and risks• General contraindications• Metabolic effects• Initiation, switching and back-up• Return of ovulation• Follow-up
Ref 1-5
Vorführender
Präsentationsnotizen
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.
Topic CHC IV: CVR-CTP
Advantages ring and patch > pill• No enzymatic degradation in the gastrointestinal
tract• No first-pass hepatic metabolism• Lower hormone doses needed• No daily peak and troughs of plasma hormone
levels• No need for daily self-administration• No daily user compliance• No difficulty swallowing pills
Vorführender
Präsentationsnotizen
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.
Topic CHC IV: CVR-CTP
Contraceptive failure ratesMethod % of women experiencing an unintended pregnancy within first year
Patch is less effective in women with body weight ≥90 kg! Ref 1- 12
Vorführender
Präsentationsnotizen
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. Fertil Steril 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 with oral 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 Steril 2016;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 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.
Topic CHC IV: CVR-CTP
Dosing errors ring and patch• Extension of ring- or patch-free week• Unscheduled removal ring or detachment patch
o apply new device asapo keep originally scheduled dayo ≤48 h: no additional contraceptiono >48 h:
7 days additional contraception If unprotected sex took place
– During previous 5 days in hormone-free interval– Any day in week 1
Consider emergency contraception– Any day in week 3
Omit the ring- or patch-free week
Ref 1
Vorführender
Präsentationsnotizen
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.
Topic CHC IV: CVR-CTP
Differences between ring and patchRules for forgotten removal
Vaginal ring
• Up to 35 days: no additional contraceptiono <28 days, ring-free week possibleo 28-35 days: no ring-free week possible
Transdermal patch
• Up to 2 days: no additional contraception
• > 2dayso Additional contraception or avoid sex for 7
days, eventually ECo Keep same patch change day
Ref 1-4
Vorführender
Präsentationsnotizen
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 2016 4. 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.
Topic CHC IV: CVR-CTP
Concurrent useVaginal ring
• EE and ENG levels not altered by Spermicide (nonoxynol-9) Tampons Antibiotics (amoxicillin,
doxycyclin)• EE and ENG levels
increased by Miconazole
Transdermal patch
• EE and NGMN levels not altered by Tetracycline
Ref 1-6
Vorführender
Präsentationsnotizen
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 rings to be used continuously for contraception and to prevent HIV infection (dapivirine-containing vaginal ring).
Topic CHC IV: CVR-CTP
Vaginal ring• Equivalent or superior
Less frequent spotting and breakthrough bleeding
Prolonged or frequentbleeding is less likely
Early or late withdrawalbleeding is less likely
Improved cycle control after switching from pill or patch
Superior cycle control in women with dysfunctionaluterine bleeding
Transdermal patch
• Equivalent or inferior Unscheduled bleeding
common in first two cycles After two cycles, similar
pattern spotting and breakthrough bleeding
At six months, unscheduledbleeding declines and remainsstable
Cycle control compared with the30μg EE pill
Ref 1-16
Vorführender
Präsentationsnotizen
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 Gynecol 2004; 104:555. 4.Westhoff C, Osborne LM, Schafer JE, Morroni C. Bleeding patterns after immediate initiation of an oral compared with 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 Reprod 2006; 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 Diagn Res 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 transdermal contraceptive patch vs an oral contraceptive: 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 Biol 2005; 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. 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.
Topic CHC IV: CVR-CTP
Acceptability compared with pillVaginal ring
• Satisfaction 84%-96% o Easy to useo Once-a-montho Remains effective if removal
and reinsertion are not in time
o Low systematic hormonelevels
o Rapidly effectiveo Reversible
• Improved psychosexual function in most RCTs
Transdermal patch
• Satisfaction higher thanwith the pill (OR 1.35: CI 1.09-1.68)
Ref 1-12
Vorführender
Präsentationsnotizen
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 combined contraceptive 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 ethinyl estradiol 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 Gynecol Reprod Biol 2005; 121: 202. 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. 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 satisfied with their method than pill users.
Topic CHC IV: CVR-CTP
Compliance compared with pillVaginal ring
• Adherence: 80%-90%• Discontinuation rate: 28%-35%• Side effects as reason: 11%-
30%• Randomised controlled trials
o ring users less likely todiscontinue (12% vs 22%)
o no differenceo using „quick start“: ring users
less likely to discontinue (11% vs 16%)
Transdermal patch• Adherence superior to the pill:
89% vs 79% (OR 2.05; CI 1.83-2.29)
• Discontinuation rate higher (58% vs pill 47%) (OR 1.59; CI 1.26-2.00)
• Side effects as reason higher(OR 2.28; CI 1.61-3.25)
Ref 1-11
Vorführender
Präsentationsnotizen
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: a randomized 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.
Topic CHC IV: CVR-CTP
Side effects compared with the pillVaginal ring
• Systemic side effectsgenerally similar
• Breast tenderness and nausea less frequent
• Less acne compared withEE/LNG pill
• No differences in headache or weight gain
Transdermal patch
• Systemic side effectsgenerally similar
• Breast tenderness (firsttwo cycles), nausea, vomiting, and dysmenorrhea morefrequent
• Less moodiness• No differences in
headache or weight gain
Ref 1-9
Vorführender
Präsentationsnotizen
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 ethinyl estradiol 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: 2347 7. 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.
Topic CHC IV: CVR-CTP
Device-related problemsVaginal ring
• Local vaginal symptomso Vaginitiso Vaginal wetnesso Vaginal discharge (17%)o No increased bacterial vaginosis
• Device related eventso Europe 4.1%, 4.7%, 6.6%,
• Expulsion rateso Switzerland 1.7%o The Netherlands 6.0% (negative
relation with ease of insertion)o USA 9% - 20%o Africa 14% Counsel women to check
• During intercourseo (13%-16% remove ring) Reinsert within 3 hours
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 Gynecol 2004; 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: 2347 12. 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 bacterial vaginosis 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 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.
Topic CHC IV: CVR-CTP
Acceptability ‘ring vs patch’: RCT• Continuation 3 cycles
o per protocol population: 94.6% vs 88.2%, p=.03o Intention-to-treat population: 91.6% vs 83.7%, p=.03
• Reason for discontinuation o Ring: discomfort, adverse effectso Patch: adverse effects, skin irritation, problems with adherence
• Plan to continue method after 3 cycles: 71.0% vs 26.5%, p<.001• Adverse effects:
o Ring: frequent vaginal discharge, bothersome with sex to user or partnerso Patch: longer periods, increased dysmenorrhea, frequent nausea, frequent
mood swings, frequent skin rash• Device-related problems ‘at least once during any 3 week use
period’o Ring was ‘expelled’ 20.4% vs patch ‘fell off’ 46.0%, p<.001
• Satisfaction: 78% vs 39%, p<.001Ref 1
Vorführender
Präsentationsnotizen
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.
Topic CHC IV: CVR-CTP
Same VTE risk for ring and patchStatement of the European Medical Agency 2013
Ref 1-7
Vorführender
Präsentationsnotizen
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 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.
Topic CHC IV: CVR-CTP
Arterial thromboembolismVaginal ring
• No significant difference compared with multiple types of pills
Transdermal patch
• No significant difference compared with NGM pills
Ref 1-4
Vorführender
Präsentationsnotizen
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.
Contraindications: Dermatological problems Overweight women Diabetic womenLower estrogen exposure
Better cycle control
Extended regimen possible Extended regimen not advised
Vorführender
Präsentationsnotizen
Gupta N, Corrado S, Goldstein M. Hormonal contraception for the adolescent. Pediatr Rev 2008; 29:386. 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.
