NuvaRing: a vaginal contraceptive

Transcription

1 Expert panel discussion 17 NuvaRing: a vaginal contraceptive ALI KUBBA, IGNACIO LETE AND PAULA BRIGGS Although the combined oral contraceptive pill is by far the most widely prescribed contraceptive option, it does not suit all women and, being user-dependent, tends to fail women who cannot stick to a daily routine. NuvaRing is a vaginal contraceptive, a hormone-containing ring that has shown good effi cacy and tolerability. Its alternative method of delivery may appeal to younger women, thus helping to reduce the high rate of unplanned pregnancy in the UK. In this expert panel discussion, three specialists discuss the new product and its place as a contraceptive choice. The panel included Dr Ignacio Lete, a gynaecologist from Spain where NuvaRing has been widely used since Mr Ali Kubba, MB ChB, FRCOG, FFSRH, Community Gynaecologist, Guy s Hospital, London. Dr Ignacio Lete, MD, Gynaecologist, Head of Gynaecological Department, Hospital Santiago, Vitoria, Spain. Dr Paula Briggs, MB ChB, MRCGP, FFSRH, DMJ(Clin), GP; Clinical Lead for Sefton Community Sexual Health Service, Liverpool. ALI KUBBA: Ignacio, could you start by telling us about your experience with the NuvaRing in Spain? IGNACIO LETE: The main reason for the success of NuvaRing in Spain, after its launch in January 2003, was that we talked about it. When women asked about contraception, they were given information about the full range of options, including the vaginal ring. ALI KUBBA: When a woman in your region of Spain requires contraception, does she go to a gynaecologist in a hospital or to a family doctor? Who is actually prescribing the NuvaRing? IGNACIO LETE: Gynaecologists usually prescribe the NuvaRing. ALI KUBBA: And Paula, I believe that you have some experience with the ring in general practice? PAULA BRIGGS: Most of my experience is in the community, but I am registered as a restricted principal GP with a prescription pad. So essentially, I am a GP with a special interest. I am quite passionate about choice and if we can do anything to reduce the high teenage pregnancy rate in this country, we need to support all women being offered the ring as a contraceptive choice. ALI KUBBA: NuvaRing is a new product in our community reproductive and sexual health service, so I use it on a small scale in my specialist clinic. Let us talk now about the product characteristics. It is a combined hormonal contraceptive ring; it uses a novel method of delivery through the vagina; it delivers the hormones for three weeks, followed by a week without the ring and then a new ring is inserted. It is soft, thin and quite small, the size of a small diaphragm. It is definitely a welcome addition to the contraceptive menu, providing another choice for women. Ignacio, would you explain the pharmacokinetics and the hormone release profile? IGNACIO LETE: The vagina is used to administer drugs to avoid the hepatic first-pass effect. The ring has some similarities with the combined oral contraceptive pill: oestrogen and progestogen are used in both; they are both a systemic form of contraception; they have the same mechanism of action and consequently the same contraindications. 1 ALI KUBBA: Because the ring is a sustainedrelease delivery system, plasma levels of oestrogen and This Expert Panel Discussion was supported through an unconditional educational grant from Schering-Plough. Schering-Plough provided funding to cover administrative, logistical and editorial support. Editorial control resided with the panel members and the publisher. Trends in Urology Gynaecology & Sexual Health January/February 2010

2 18 Expert panel discussion thinking that the efficacy of the vaginal ring is similar to that of oral contraception? IGNACIO LETE: Dieben et al. 4 looked at efficacy in a non-comparative study, and other studies have compared the ring with an oral contraceptive containing levonorgestrel 5 and also with an oral contraceptive containing drospirenone. 6 In these studies, the Pearl index of the ring ranged from 0.24 to 1.23, and that of the pill was between 0.5 and So we can conclude that the ring is as effective as the pill. NuvaRing is a combined hormonal contraceptive ring. progestogen are more constant than those in pill-takers. In addition, if we look at the area under the curve, serum ethinylestradiol levels are about 40 per cent lower in ring users compared to women taking oral preparations. 2 IGNACIO LETE: Jensen et al. 3 compared the impact of switching from oral to transdermal patch or vaginal ring contraception on biomarkers of thrombosis, and their conclusions were that oral contraception users who switch to the ring exhibit beneficial changes in such biomarkers. Probably we cannot link these results with the information from the van den Heuvel study, 2 in which the area under the curve of ethinylestradiol was 3.4 times lower in NuvaRing users than in patch users and 2.1 times lower than in pill users, but it is important to note that the NuvaRing provides a lower exposure to oestrogen. That could prove to be an advantage, but we do not have enough clinical data to be sure that the safety profile of the product will be better than that of the pill. ALI KUBBA: It looks like a genuine advantage in theory, because if you are using a method that bypasses the liver, you have less first-pass effect, but it s also delivering a lower, although still effective, level of oestrogen. From a safety point of view, at least theoretically it may have an advantage, but I agree that we need a lot of epidemiological data to support any claim of extra safety. PAULA BRIGGS: We need to be very careful that people do not think this is a contraceptive method for women who are heavier or who have risk factors. ALI KUBBA: That is absolutely right. Looking at efficacy and comparative efficacy, would I be right in PAULA BRIGGS: People will be reassured by the message that the ring is similar to the combined pill, but obviously it has some added advantages. The pill probably fails because women do not remember to take it. That problem may be avoided with use of the NuvaRing. ALI KUBBA: Yes, if you look at the intention-to-treat data, the pill is as effective as the ring, but the typical user failure rate is higher. PAULA BRIGGS: Lots of women miss lots of pills and I personally am concerned about the guidance from the Clinical Effectiveness Unit of the Faculty of Sexual and Reproductive Healthcare (FSRH) about how many pills women can miss in an individual pack. 7 The benefit of NuvaRing is the consistency of hormone levels and the good cycle control with a minimal amount of oestrogen. I do not doubt that NuvaRing is a good method. My anxiety is that women in the UK do not appear to be keen to consider it as an option. ALI KUBBA: If we look at the attributes of NuvaRing, it has many of the advantages of the oral contraceptive pill: it is under the user s control; it inhibits ovulation; it is effective. But it also has some of the features of the long-acting reversible contraceptives (LARCs) in the sense that it does not need frequent/regular action by the user. However, what distinguishes it clearly from LARC methods is that it is under the user s control. So it puts the woman in charge of her contraception. That is an important requirement for many women. IGNACIO LETE: In all the clinical trials, the compliance among pill users was very similar to that among ring users. We can probably predict that in real life the compliance with the ring will be better than that with the pill, but we do not have data based on clinical trials to confirm that. Trends in Urology Gynaecology & Sexual Health January/February

3 Expert panel discussion 19 ALI KUBBA: That is the obvious difference between women who use contraception in real life and those who take part in clinical trials. But it is reassuring that in comparative clinical trials the ring had very similar outcomes to the pill. The discontinuation rates were very similar in the studies. Acceptability and tolerability were also quite high in both. Turning to tolerability, is there a difference in the side-effect profile, comparing the ring with oral contraception? IGNACIO LETE: Roumen 8 looked at studies comparing the pill and the ring: the percentage of women reporting oestrogen-related side-effects was very similar in the two groups. There was a lower incidence of side-effects among ring users, but this was not statistically significant. On the other hand, the local effects were higher in the ring users. ALI KUBBA: Women should be warned about these local effects, by which we mean an increase in vaginal discharge. IGNACIO LETE: Yes, but this vaginal discharge is uncommon, affecting only 5 per cent of women. 8 ALI KUBBA: On the same theme, although there is a small increase in women reporting vaginal discharge, if you look at the lactobacilli population in the vagina, for instance, it actually increases with use of the NuvaRing. 9 So, theoretically, the ring may have some advantage in the sense that it maintains the ecosystem in the vagina. IGNACIO LETE: Of course, and Archer demonstrated that NuvaRing does not increase vaginal infections. 10 Another potential advantage of the increased vaginal moisture caused by the ring is that it could improve vaginal dryness in perimenopausal women. ALI KUBBA: Let us discuss retention and expulsion rates. Some women are concerned that gravity will cause the ring to fall out. I explain that this is unlikely, as it is placed in the upper third of the vagina, which is horizontal rather than vertical. PAULA BRIGGS: One of my patients said that the ring fell out every time she had sex. I assumed that she did not have it in properly. ALI KUBBA: The ring does not need any special fitting; women just introduce it themselves. However, women with prolapse are more likely to expel it than KEY POINTS NuvaRing is a combined hormonal contraceptive ring. It delivers 15µg ethinylestradiol and 120µg etonogestrel every 24 hours. It is inserted once during a cycle for three weeks, then removed for a week and a new ring inserted. It is 54mm in diameter and 4mm thick. A cold chain must be used to keep it at 2 8 C until it is dispensed. Novel delivery method, using the vagina to avoid the hepatic first-pass effect. Sustained-release delivery system. Similarities with the oral contraceptive pill (use of combined hormones, systemic delivery, same mechanism of action and contraindications). Leads to 40 per cent lower levels of serum ethinylestradiol compared with oral preparations. Efficacy is similar to that of oral contraception. those with good vaginal tone. Is expulsion an issue for your patients in Spain, Ignacio? IGNACIO LETE: No. We published a paper in 2007 (the Etna study), 11 which included 805 women. Of them, only one (0.12 per cent) discontinued using the ring due to expulsions. The percentage of women reporting ring expulsion is around 2 per cent, very similar to the percentage of women reporting tampon expulsion. ALI KUBBA: With the expulsion rate being between 1 and 2 per cent, you mentioned low discontinuation due to expulsion in your study; more women probably reported occasional expulsion but carried on using it because, obviously, if the ring falls out all you need to do is to wash it and put it back in. ALI KUBBA: Cycle control is an important attribute of the ring. Paula, would you like to talk about this? PAULA BRIGGS: In my experience, cycle control appears to be better in women using NuvaRing, despite the lower dosage of oestrogen. None of my patients has discontinued using it because of problems with cycle control. Problems have occurred, however, when women present to other organisations with vaginal discharge. One woman with discharge went to hospital and was told she had an infection, which was not the case; women need reassurance that this is normal. Trends in Urology Gynaecology & Sexual Health January/February 2010

4 20 Expert panel discussion PRACTICAL COUNSELLING TIPS FOR USERS Under the control of the woman. No need to remember to take daily pills. Convenient, comfortable and easy to use. Better cycle control than oral contraception. Possibility of increased vaginal discharge. The vagina is an ideal place to deliver a hormonal contraceptive. The NuvaRing is a safe and effective method of contraception. Other side-effects similar to those of oral contraception. Minimal awareness for the male partner during intercourse. IGNACIO LETE: We have considerable data regarding cycle control when using the ring. In Roumen s study, fewer than 5 per cent of women had intermenstrual bleeding. 12 Oddson 13 and Bjarnadóttir 14 compared the ring with combined oral contraceptives. Sabatini 15 compared the ring with two types of pill, one containing 20µg ethinylestradiol and 100µg levonorgestrel, and the other containing 15µg ethinylestradiol and 60µg gestodene. Among ring users, 4 9 per cent of women presented with irregular bleeding, while in the 15µg ethinylestradiol pill group, per cent of women had irregular bleeding. So the ring provided better cycle control using the same amount of ethinylestradiol. ALI KUBBA: The FSRH Clinical Effectiveness Unit has highlighted the fact that NuvaRing has better cycle control than oral contraception. 16 In my specialist clinic, the small number of women referred with cycle control problems on oral contraception cease to have problems after switching to the ring. PAULA BRIGGS: Antibiotics such as amoxicillin and doxycycline also cause irregular bleeding in some women on the pill. In ring users, taking these anti biotics will not affect efficacy or cycle control. IGNACIO LETE: How is such good cycle control obtained by using such a low dose of ethinylestradiol? ALI KUBBA: The large surface area of the vagina is highly effective at absorbing the hormones; therefore, very constant levels are obtained. We know that the endometrial effects are as you would expect with the combined pill. The ethinylestradiol is not affected by any changes in the absorption patterns from the bowel, which is what you would see with oral contraception. Ignacio, do you think that the proximity of the vagina to the endometrium helps to explain how such a low dose of ethinylestradiol provides effective contraception and good cycle control? IGNACIO LETE: Yes, and here we can refer to the uterine first-pass effect described by Cicinelli. 17 According to this theory, the ethinylestradiol delivered from the ring goes directly to the endometrium in a first step and then goes through the blood stream. We use ethinylestradiol in combined hormonal contraceptive methods to stabilise the endometrium, so having constant and stable levels of ethinylestradiol at target tissue could provide a better cycle control. ALI KUBBA: However, we can reassure users that there are no adverse endometrial effects such as endometrial hyperplasia. 18 Which women will the NuvaRing suit? What is the typical user profile? PAULA BRIGGS: It should be offered to all women the person it will suit is the person who is willing to give it a go. Young women may hear of the ring through word of mouth and attend asking for it. If offered proactively in a young person s service, uptake could be significant. ALI KUBBA: It is particularly suited to young people who want a method that does not require daily action. Users who register with a website receive a reminder by text message when it is time to change the ring, thus minimising the risk of user failure. Ignacio, do you think previous experience with vaginal applications, such as female barriers, is necessary? Or would you just explain to women that it is as easy as using a tampon? IGNACIO LETE: In the Basque Country, nearly 98 per cent of women use tampons during menstruation, so they are comfortable touching their genitals. However, it is not necessary to have previous experience. In the Etna study, 25 per cent of women who chose the ring did not have any experience in the use of tampons and they used the ring without any problems. 11 PAULA BRIGGS: One of my patients came to get extra gel for her cap. When I talked to her about the ring, she was very interested because clearly she was happy using a vaginal delivery system. ALI KUBBA: In the Novak paper, 25 per cent of women gave the primary reason for using the ring as ease of use. 19 About 45 per cent said that they wanted to use it because they did not want to have to remember Trends in Urology Gynaecology & Sexual Health January/February

5 Expert panel discussion 21 to take regular action. So ease of use and practicality are big advantages, and this is one way of mainstreaming the use of the NuvaRing in the population in this country. PAULA BRIGGS: Ali, the point that you made earlier about the ring being under the user s control is really important. The Implanon implant is very popular, but some women ask for it to be taken out just to see whether removal is going to be a problem. At least with the ring, removal is within their control. Essentially it is a LARC giving women a month of contraception without loss of autonomy. ALI KUBBA: It compares well to other contraceptives that are popular with young people, such as the implant, as it has the features of a long-acting, or at least medium-acting, contraceptive. Young people like it because it fits in with their lifestyle. But what about women at the other end of the spectrum the over 35s does it have any special attributes for that population? IGNACIO LETE: We have a very good acceptance rate in all women. But the profile of ring users at least in our experience is the same as that of all users of hormonal contraception. They tend to be women between 20 and 35 years of age, including students and working women. But we also have a very good acceptance rate in women over 40 years. It improves vaginal moisture and reduces vaginal dryness. One reason why women want to change to the intrauterine device or the implant is that they are fed up with taking the pill every day. ALI KUBBA: From our discussions, I think we agree that the ring should be considered a first-choice method: it is safe, practical, easy to fit and remove, and fits in with the lifestyle of women of different ages. PAULA BRIGGS: People will always make an issue about cost, but many women have Implanon inserted and then insist on its removal, which is a costly process; the same is true for women who forget the pill and get pregnant. So I think we can justify the cost. ALI KUBBA: In the LARC guidelines published in 2005, 20 the National Institute for Health and Clinical Excellence said that any long-acting contraceptive would be cost-effective if kept in for a year. The cost of the intravaginal ring over a year is comparable to the other LARCs such as Mirena and Implanon, as well as having the extra features we have been discussing. ALI KUBBA: For the professionals in this country, Ignacio, what would you say persuaded the Spanish gynaecologists in the Basque Country to promote the NuvaRing? IGNACIO LETE: NuvaRing is as effective as the pill; it has the same contraindications, but the safety profile is a little better. Women want a convenient method, a comfortable method, and this modern type of contraception has been accepted and evaluated by Spanish gynaecologists. New types of pills appear regularly, with a few minor changes in content or dosage, but with no real improvement in efficacy or tolerability. So the ring is a modern method that could meet the modern woman s needs: efficient, convenient, comfortable and easy to use. ALI KUBBA: I would like to discuss the issue of whether the method is acceptable to the male partner, because in some cultures that has been an anxiety with vaginal methods. What do you say if the woman asks whether her partner will feel the ring during intercourse? PAULA BRIGGS: We have seen couples together where clearly the male was very anxious about the idea of a vaginal ring. This provides an opportunity to talk to the couple about the safety of the ring and the fact that it will not affect them during intercourse, and even if they can feel it, this will not cause any problems. ALI KUBBA: I explain to patients that, while the vagina is a very good absorbing surface, the penile skin does not absorb hormones so well, so the male partner is unlikely to be affected. The discontinuation rate of the NuvaRing because of male awareness or male discomfort is actually quite small. IGNACIO LETE: I do not know of any couples who have discontinued using the ring for this reason. More than 80 per cent of male partners say that they do not feel the ring during intercourse. In addition, Sabatini concluded that sexual satisfaction when using the ring was better than when using an oral contraceptive. 15 ALI KUBBA: How do we facilitate the provision of the NuvaRing in the UK healthcare system? I am talking about formularies versus FP10s; the cold chain; issues around cost. PAULA BRIGGS: We are in a very fortunate position with NuvaRing because Spain has seven years experience, which is better than any postmarketing surveillance study. So that takes any anxiety about its efficacy and safety out Trends in Urology Gynaecology & Sexual Health January/February 2010

6 22 Expert panel discussion of the picture. The issue will be the practicalities concerning the cold chain, and though this could be potentially problematic, there are solutions. In addition, the ring is relatively bulky, so it will be difficult to keep large quantities in any one clinic. GPs are being encouraged to review their formularies, clearly for financial reasons, but it is important that this product is included in formularies because it is the only method with this particular delivery route, it is low dose and has LARC features. So it will be necessary for specialists to be involved with medicine management groups to ensure that NuvaRing is there as a choice for primary care. But at the end of the day, GPs can prescribe what they want. So it will be excellent to get this message across to GPs that the ring is here in this country; it is safe; it has the same contraindications as the combined pill; it is highly efficacious, with some definite positive advantages for patients. ALI KUBBA: Because it is a novel delivery system, we need to legitimise it by submitting formulary applications and negotiating with our management teams. But the other side of that equation is to say that the FP10 facility allows you to prescribe it, and the pharmacist to supply it, because this avoids any anxieties about cold chain and about having large stocks in fridges. ALI KUBBA: To summarise, I think we all agree that the NuvaRing appeals across the age spectrum and across the usage spectrum. A LARC user may find it more attractive because she has autonomy over the method; an oral contraceptive user may prefer it because she can get away from a daily routine. Declaration of interests Ali Kubba lectures and has received honoraria for advisory work for Schering-Plough and other pharmaceutical companies. He has been sponsored to attend scientific meetings. Ignacio Lete has been a speaker at several symposia sponsored by Schering-Plough, Bayer and Wyeth. Paula Briggs has received honoraria from Schering-Plough (Merck), Bayer Schering and GSK, and has attended medical meetings as a guest of these different pharmaceutical companies at different times. References 1. Mulders TMT, Dieben TOM. Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition. Fertil Steril 2001;75: van den Heuvel MW, van Bragt AJM, Alnabawy AKF, Kaptein MCJ. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005;72: Jensen JT, Burke AE, Barnhart KT, et al. 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The combined contraceptive vaginal ring (NuvaRing) and endometrial histology. Contraception 2005;72: Novak A, de la Logeb C, Abetzc L, van der Meulena EA. The combined contraceptive vaginal ring, NuvaRing: an international study of user acceptability. Contraception 2003;67: National Institute for Health and Clinical Excellence. Long-acting reversible contraception. Clinical Guideline 30, October Trends in Urology Gynaecology & Sexual Health January/February