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And my task for this afternoon is to review for you a new contraceptive option and what I’d like to do first is show you my disclosure statement and then I will go into the first part of discussion, talk about why I think there’s a need for this new contraception option and then go in much greater depth in discussing it.
Certainly, these are exciting times from the standpoint of what’s been available for people working in this field. If I were to give this talk, say, a decade ago, certainly there were not a lot of new approaches that were available. But for the first time, in what I would say two or three decades, there actually are new delivery systems and significant modifications of existing systems.
But is there a rationale? Is there a need for these new systems and I think this next slide says it all. If you look at the unintended pregnancy rate in this country, despite improvements that we’ve had in the past two to three decades, clearly one-half of the pregnancies at least in the United States are either unplanned or unintended and if you look at this pie chart, you can also see that over 50% of the pregnancies result in an induced abortion and about 45% of the pregnancies last until delivery. Clearly, a significant and economic and social problem for this country. If you further analyze unintended pregnancies, you can see that 40% of the pregnancies occur among individuals who do not desire to have children at that time, yet aren’t using a method of contraception.
Is this a matter of past experience mean a problem? Is this a matter of motivation? Whatever the answer is, obviously it is a significant contributor to unintended pregnancies. Sixty percent of the pregnancies occur among individuals who are using some method of contraception in the month prior to the pregnancy. Is this a matter of inability to use the method correctly? Is this a matter that side effects can interfere with individuals’ understanding of using the method? It’s a complex subject but clearly some of the new methods that, in fact, link them to dosing schedule may, in fact, be important in allowing women and couples to successfully use contraceptive methods.
If we look at the consequences of unintended pregnancy, certainly those of you who are still practicing obstetrics despite all the court problems that we’re having, clearly understand that there are certainly significant problems, going from missed periods to ectopic pregnancy, certainly gestational diabetes, hemorrhage, infections, pregnancy inducement, hypertension, roughly 20% of women require major surgery if they go on to deliver. Also, the timing of pregnancy may not be ideal if it’s unintended and certainly one has a lost opportunity for preconceptual counseling. Things like counseling and dealing with chronic diseases so that an individual is in their best possible shape. Certainly diseases like hypertension and diabetes, dealing with occupational exposure, attending to rubella immunization if that’s required, making sure that there’s adequate folic acid(Drug information on folic acid) supplementation and certainly one can go down this list. So again, enforced aspects of trying to avoid unintended or unplanned pregnancy.
Overall, if you look at the magnitude of pregnancy in the United States, there are about six million women who become pregnant and half are unplanned. Every day, approximately 10,000 women in the United States give birth and the CDC estimated, estimates that there are two to three deaths each day due to pregnancy-related complications. There are about 2,100 antenatal problems, 2,500 caesarian sections each day and about 2,600 major labor-related problems. If you express it like this to the unplanned, unintended group, this would be about one woman today died because of an unintended pregnancy, about 670 had an antenatal complication, 800 women had a caesarian section today all because of an unintended or unplanned pregnancy. A significant contributor to the public health issues of this country.
Certainly there are properties of contraceptive desires by women. Certainly you want a contraceptive that is highly effective, ideally prolonged duration of action, certainly you want contraceptives that are rapidly reversible, you certainly want privacy of use. In general, women in this country really do not want amenorrhea and, if possible, protection against sexually transmitted illnesses. Currently, certainly, a lot of positive trends in the development of new contraceptives. As we will discuss today, there are new delivery systems for the first time, and also by having new delivery systems and improved systems, certainly there are far greater options available to couples now than there ever were before. Also, I think many of these new systems clearly indicate the client, that is the ability to correctly use the method, is improved and we’ll show that shortly about that. Certainly we must not forget to also be sure to widen the use of emergency contraception and certainly this state is one of the state that certainly has sort of led the pack, so to speak, in making emergency contraception available and certainly we need to recognize the importance of non-contraception benefits, all of which that I think make certainly contraception much more palatable for our patients.
We look at some of the new available methods of contraception. Here are four of the new methods. Certainly the injectable contraceptive, its duration is one month and, as shown here, has an excellent pregnancy rate, that is, efficacy rate. There is certainly the new levo Norgestrel releasing IUV, has a duration of action of five years, also has excellent efficacy. There is a new vaginal ring that has been available now for a couple of months. Again, is a monthly system, also with an excellent efficacy rate, and what we’ll be spending most of our time talking about is the Transdermal Contraceptive Patch which is essentially a weekly system, also with a superb efficacy rate. We look at a couple of these just briefly.
Certainly the levo Norgestrel releasing IUV, as already mentioned, certainly has excellent efficacy over the five-year span of its use. It does have a different bleeding pattern than the Copper E280A in that the bleeding tends to be somewhat less predictable and, in fact, in the first few months of use tends sometimes to be heavy, but again this then, sort of, reverts to spotting such that, at a year to years out as many as 20% to perhaps even 25% may be amenorrhea. Certainly, although it releases levo Norgestrel, the levels systemically are quite low but, and obviously require clinical interaction for insertion and removal.
The injectable system, the new system that it combines an estrogen and a progestin, is also highly efficacious, it is associated usually with regular, monthly menstrual cycles, it does require, however, sort of a timeframe of 28 days, plus or minus five days, for injection so it does require that there be a system in place for patients to present to their healthcare provider to obtain the injections and, unlike the progestin-only injectable, return to fertility is quite rapid after it’s discontinued and this week there’s actually a new oral contraceptive that is now becoming available.
Most of you are aware of the new Drustironome, the contraceptive that’s been available for several months. This is a new norgestimate(Drug information on norgestimate) oral contraceptive that essentially has the same sort of pattern of norgestimate as the 35mg pill, but the dosage of the estrogen has been reduced to 25mg. In clinical trials, it’s highly effective. The tolerability, that means the side effects of this particular reduced dose oral contraceptive is similar to the comparison, comparator 20mg pill and it has a superior cycle control and certainly in the clinical trials, comparing it to a 20mg pill in roughly ten out of thirteen cycles evaluated, this pill did better and, in fact, if you look at data from the clinical trials of this 25mg pill versus the current 35mg pill, you can see that the bleeding patterns look relatively the same, so that hopefully for many of our patients, one will have the opportunity to have a pill that has less estrogen and hopefully reduce the estrogen-related side effects yet maintain excellent cycle control, a problem sometimes that one has with a lower dose estrogen OCs.
We have a new vaginal ring that’s been available for general use for two to three months now. It contains a progestin hemonorgestrel which is the major metabolite of begelgestrel and ethinyl estradiol(Drug information on estradiol). This speeds up the release rates. It basically is a system that you wear for three months, or, excuse me, three weeks out of four weeks and then it requires self-insertion and removal and it has a pregnancy rate that’s very comparable to what one would see with oral contraceptives. Highly efficacious and obviously a question that is, that people can raise is that since this is a sort of continuous release system, does weight affect the efficacy and we’ll cover this issue in a little more detail when we talk about the transdermal system. Unfortunately, in doing the clinical trials with roughly 2,200 subjects, there were only twenty subjects that were in the weight range where this could be analyzed and obviously this is insufficient on numbers of individuals because of height selection criteria. The average weight of women in the clinical trials with the ring was 138 pounds and the average BMI was about 23, so very restricted population that was studied. So we have very little data as to whether or not weight will affect its efficacy. Certainly there is good cycle control with the ring, irregular bleeding is relatively uncommon and withdrawal bleeding occurs regularly and also compliance was net in about 90% of subjects, something that I think is very important.
This now brings us to where we’ll spend most of our time and that’s the new Transdermal Contraceptive System. This is a system that’s been available now for a little over five months. It consists of a patch that is 20cm square, it is a matrix system, there’s an outer protective layer, there’s a middle layer that contains the contraceptive steroid as well as the glue and then there is a peel-back layer that is used to peel back and apply it to the skin. It can be applied to four sites as shown here: the abdomen, also can be applied to the buttocks, the upper torso except for the breast, as well as the outer arm. Why the 20cm square? Actually, a 10cm, a 15cm and a 20cm square patch were studied, but it was this patch that had LUD levels of steroids that consistently inhibited ovulation, also kept estrogen levels and gananprofen levels reduced against progestin that was efficacious. If you look at the administration schedules outlined here, basically this is a weekly contraceptive as opposed to, say, an oral contraceptive which is daily. An individual, for example, might apply on the Sunday, go to the next Sunday, remove the patch and reapply a patch for the next Sunday, remove and reapply, and on the fourth Sunday after the three patches, it would be removed and then one would have a hormone-free interval where, in fact, withdrawal bleeding would occur. So again, in a sense, mimics an oral contraceptive cycle but the dosing frequency is only three doses in a sense as opposed to the 21 doses of contraceptive steroids that you have with a pill. The patch has norgestermin, which is the major metabolite of norgestimate and ethinyl estradiol. It delivers the steroids at the rate shown here. Many people in looking at this data would say, well, this appears to be like a 21mg pill in a patch. But, again, you have to keep in mind that the pharmokinetic of continuous release systems are far different than the sort of peak and valley sort of systems that you have with an oral preparation, so direct comparability is really not possible in terms of looking at a pill versus a transdermal system.
If you look at why norgestimate was selected, it’s the most widely used progestin in oral contraceptive, it certainly has a long established safety profile in this country, as well as in Europe. It certainly has minimal systemic effects and certainly maintains excellent cycle control. If you look at the pharmacokinetics of this particular system, you can see in the far left-hand portion of the slide once the patch is applied, very rapidly the steroid levels reach the reference range. This is the range in which ovulation is inhibited and over the seven days that the patch is applied, they stay within that range. Once the patch is removed, you can see the levels fall off rather dramatically to almost undetectable levels within a day or two. In contrast, if you look at the middle of the slide, this is an individual who is taking an oral preparation with the same steroids and you can see the difference in the pharmacokinetics and if you have the wide peaks and falls with an oral preparation as opposed to one of these continuous release systems. Also there is built-in some reserve with this particular system.
In this particular study, individuals who used the patches appropriate for the first seven days then reapplied, but with the second patch were asked to have the patch remain on while steroid levels were measured and, as shown here, there’s roughly a two-day period of time when, in fact, the levels stayed within what is known as the reference range, the range of steroid levels felt to inhibit ovulation and prevent pregnancy and as Dr Shulman will talk with you a little bit later, this is important in some of the counseling that you have with patients. Are the sites equivalent, whether you put it on the buttock, the arm, torso, upper or lower and, as this data shows you, this is just the norgestimate or norgestermin data, you can see that the sites are essentially equivalent. What about activities? How does vigorous activity or humid conditions affect the pharmacokinetics of the patch? In this particular study, thirty individuals were asked to perform a variety of activities that are common to sort of a health club and were asked to wear the patch for seven days and before they performed another activity had a ? wash-out and, as shown here where, for example, the ethinyl estradiol levels were measured whether you were doing a combination of activities where swimming in cool water, sauna, treadmill, whirlpool, you can see that again the pharmacokinetic profile was similar regardless of sort of the health club activity you might have taken up at the time.
Also, what was measured in part of this study was how difficult was the patch to remove? Obviously, one of the concerns would be that if you are doing activities where there’s lots of perspiration and so forth, perhaps the patch loses its adherence when, in fact, when the strange gauge measurements were used, you can see the data certainly supports that adherence is not adversely affected by these activities and, in fact, among the 87 cycles or weekly cycles, only one patch became detached out of 87. So, overall, the patch appears to have good pharmacokinetics regardless of activities, whether it be vigorous or sedentary, and it appears that the adherence rate is not affected adversely by such activities and, overall, to summarize the pharmacokinetics, it delivers levels of the norgestimate and ethinyl estradiol in a sort of a continuous fashion, unlike the peaks and falls of an oral medication. It delivers the steroids at the rates highlighted with a second bullet and it certainly can maintain the serum concentrations of the steroids in the appropriate range for as long as nine days. The four anatomic sites are equivalent, the concentrations are such that there is no accumulation in the second or third week from the use of the drug and activities do not appear to adversely affect the pharmacokinetics.
So, how long does it work and is it a safe preparation? These are three studies that have been published. The first one by Smallwood is not a comparative trial. The second two studies by Hedon and Audett are trials where their comparator was an oral contraceptive and if we drop down to the total line on the bottom and look at what is indicated as the overall purl rate versus the method rate, you can see that the overall rate, which would be a typical use rate, is, in fact, very good and, in fact, is very similar to the perfect use or method rate, suggesting very clearly to me that in these various studies compliance, that is the ability to use the method correctly, was quite good and, as we will show you, self-report data would certainly confirm that.
If we break this out a little bit more with the next slide, this is data from the Audett study published a little over a year ago in JAMA, where the patch was compared to a triphasic levo Norgestrel OC, if you look at the overall purl rates with a patch versus the method purl rate, you can see that they are quite similar. In contrast, if you look at the overall rate, which is the typical use with the OC versus the perfect use rate, you can see roughly that the overall rate is about double the method rate, suggesting that compliance was better in this particular trial with the patch as compared to the OC and, as I will show you shortly, the self-report data would back that up.
One area of concern was data that looked at failure rates, that is pregnancies by week. Roughly 3,300 subjects were evaluated in the trials and they were broken up in deciles to examine what the failure rates were by body weight and you can see on two, you get up to 90kg, that there is a relatively even distribution of the pregnancies across the various weight deciles. However, among the, roughly over 80 individuals who were in that last decile, there were five pregnancies, clearly suggesting that the failure rate for people with either high BMIs or high weight is somewhat higher. Does this mean individuals of this weight, which is roughly 198 pounds or greater, should not use this method? No, it just means that they need to be counseled about the possibility that their rates of efficacy may be somewhat different and we shouldn’t be totally alarmed about this. This is an area that is under study and actually a group in Seattle did publish in the Obstetrics and Gynecology in May the results of a covert study looking at roughly 600 individuals who were part of another study and they were able to point out that among those individuals who had in the highest quartile for weight and the highest quartile in this particular study was 155 pounds or greater, they had about a one and a half times greater chance of experience a failure compared to the other three quartiles.
We look at this diagrammatically here and go to the far right hand portion of the slide, we just see that when we use the first three quartiles as the reference group and if you look at the failure rates, they’re roughly similar in those three quartiles and compare that to the pregnancy rate in the fourth quartile, that is the individuals over 70.5kg, you can see that there is about a one and a half greater risk of pregnancy for the individuals who are in this heavier weight category. This data was also broken down by types of OCs based on estrogen dose and you can see that if you follow this data all the way down, certainly the lowest dose of oral contraceptives seemed to fare less well than the higher dose. Now does this mean that this is substantial proof that weight significantly affects the contraceptive efficacy? I think this is a provocative study and a study that certainly has gotten a lot of interest. Certainly those of you who followed Northland understand that this has been an issue with that particular contraceptive years past and certainly the NICHD is also conducting a study currently to better evaluate this particular problem, but it may very well be that when we look at combination steroid products, one size, in a sense, may not fit all.
What about compliance with the transdermal patch? As shown here with data from the Audett study, you can see that roughly 88% of women using the patch worked perfectly in terms of using the patch, changing it weekly as they were supposed to, whereas only about 78% of individuals who were using the OC took it daily by their self-reported diaries and I think, again, the typical use versus measure of use, failure rates that I showed you a few slides ago I think would support this compliance data. Of further interest, however, is when you look at this next slide at compliance by age group. I would have suspected what you see with the yellow, which is the OC data, that in fact teenagers would be less compliant with the method that we see with the OC then as one ages, certainly ability to try to adhere to the method improves. When, in fact, with the transdermal patch, in fact, regardless of the age group you were in, the compliance was roughly 90%, meaning that this is a method that certainly is mainstream and can be used by all age groups successfully.
What about adverse events? If you looked on this list, these are similar to what you would see in most contraceptive studies with two obvious exceptions. Certainly application site reaction you would not see with most OC studies and this occurred to about 20% of individuals, but only 2.5% really felt that this was limiting to the point that they did not continue to use the method. In addition, breast discomfort in this particular trials, or trial, was somewhat higher than compared to OCs and about 19% of women experienced this, but only 1% felt that this was severe enough to discontinue use. In general, the breast discomfort appears to be self-limiting, appears in the first couple of cycles and then essentially the degree of discomfort is very similar to the pill use thereafter. Further, when you look at the severity of breast symptoms that the women reported, the vast majority of symptoms were classified as being mild to moderate.
What about bleeding? This is data, breakthrough bleeding data, looking at the levo Norgestrel triphasic pill versus the contraceptive patch and you can see that the data is essentially comparable. Breakthrough bleeding is a requirement for more than one sanitary product during a given cycle to protect against the bleeding. However, when you add spotting to this, which is lesser bleeding, you can see in the first cycle there is slightly more spotting with the transdermal system compared to the OC in the comparative trial. Lipid studies have been done and, in general, the amount of change that you see with this particular system is less than what you see with most OC products and overall there is no significant alteration of ratio, such as LDL to HDL. Also, the byproduct of the lipid, oops, also, the byproduct of the lipid studies, there was a placebo controlled trial where, in fact, women were followed having their lipid measurements performed but also were on the transdermal patch and were followed for nine cycles. When you look at the weight distribution, or rather the change in weight distribution after nine cycles, you can see it’s exactly the same whether you were taking the placebo or were taking the transdermal patch, indicating at least within roughly the first year this particular system does not affect body weight.
How well does it stick once it’s applied? If you look at the far left column, this is sort of summary data from the various trials and you can see that out of roughly 70,000 plus patches used, about 1.8% became completely detached and again could sometimes be reapplied and about 2.9% were partially detached. If you look at the column just to the right of the left column, you can see that this did not appear to change whether you were in a humid climate as opposed to a more northern climate. So, so, in summary, this is a new system that delivers constant levels, that is it is constantly leaking levels of contraceptive steroids. There are four therapeutically equivalent sites. The efficacy is quite comparable to oral contraceptive. Compliance with a patch and then I think an important thing, if we’re talking about trying to deal with unintended pregnancy rates, is excellent. Side effects profile is quite similar to OCs with the two exceptions I mentioned before. Overall, the detachment rate is modest and certainly daily activities do not affect the ability of the patch to say, to stay inside or interfere adversely with its pharmacokinetics.
So where are we with contraception at this point? Certainly this is the profile of what we have seen relative to contraceptive use, again going back, let’s say, five years ago. Certainly among the reversible methods, oral contraceptives certainly lead the pack and certainly we see over the years that condom use has increased, probably related to the STD concerns that individuals have had for the past several decades. Other than that, there’s a contraception certainly has sort of trailed the pack, so to speak. But if we look at data from prescription data over the past several months since this particular system was introduced, certainly OCs continue to be the most popular reversible method as the data that I just showed you would suggest. However, pharmacy sales data indicate that the transdermal patch is more frequently prescribed than most OCs and other reversible methods. In fact, if the transdermal patch were an OC, it would be the second most frequently prescribed OC in this country. So certainly as a method of, that women have sort of taken up or gotten interested in, it certainly has caught their attention. So in summary, certainly we continue searching for ideal contraceptive options. Although we have new delivery systems, I’m not sure necessarily that we’ve solved the problem. It is hope, however, that these new methods, and I think because of their dosing schedule which is less daily and less related clearly to colitis, will affect the unplanned pregnancy rates in a favorable direction. Certainly, new choices allow us as clinicians and certainly our patients can certainly adapt in using methods that certainly fits her lifestyle. However, I think continued contraception research is essential as we try to find even better and more effective methods. I thank you for your attention.