Sandra Ann Carson, MD

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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 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 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.  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.

Articles

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.

A New Contraceptive Option: A Focus on the Transdermal Contraceptive System

:   “It’s October 2002 and we are in Seattle at the ASRM and next to me  Professor Ronald Burkman.  Very  welcome.”  

:   “We just heard a presentation about one of the several new devices for  contraception and you took part in a lot of research about this Transdermal  Patches for contraception.  Can you  tell me what’s the idea behind it?  Why  a patch for contraception?” 

:   “Well, I think it is a very interesting concept.   I mean, actually in the last few years we’ve got two sorts of brand new  systems, in terms of delivery systems.  The  contraceptive patch, which is transdermal and also the vaginal ring, which is  obviously trans-vaginal.  The beauty  of the system certainly the patch has been used in hormone replacement therapy,  it’s been used for things like motion sickness, and for delivering drugs for  angina, but it’s a steady release system and the hope behind it is you avoid a  lot of the peaks and troughs that you get with an oral medication.   And that hopefully you also reduce the overall frequency of side effects  with continued use.  What’s been  noted with this particular system is that the ability of women to successfully  use this, that is adhered to sort of the dosage schedule which is weekly for  three straight weeks appears to be significantly better than, for example, their  ability to use oral contraceptives.  For  a certain vulnerable population, such as adolescents and others, this in fact  may reduce the unintended pregnancy rate which in the United States still is a  significant problem, accounting for roughly 50% of the pregnancies we have each  year.” 

:   “Yes.  Basically a girl,  woman takes it one patch each week for three weeks and then one week oppose?”  

:   “Right.  The way the patch  is it mimics an oral contraceptive from that perspective.  Again, it’s as you described, one patch weekly for three  weeks and then there is the hormone-free interval.   The patch is a matrix system.  It’s  20 cm square, contains an outer layer that’s basically for protection.   The inner or middle layer rather has the contraceptive steroids along  with the glue and then there’s a peel-back layer for its application to the  skin.  It’s been tested in four different sites, the buttocks, the  lower abdomen, the upper abdomen, obviously not the breasts, as well as the  upper, outer arm and there is certainly bio-equivalents across all those sites.   It delivers two hormones, one is Norelgestromin which is sort of the  major metabolite of norgestimate progestin that’s probably used in the most  widely prescribed OC in this country and also contains Ethinylestradiol which is  the estrogen contained in, obviously oral contraceptives.”  

:   “What’s about the daily dose delivered?”  

:   “The daily dose is about 20 micrograms of Ethinylestradiol and I think  it’s 150 micrograms of Norelgestromin.  Now  a lot of people say, ‘Well then it’s really just a 20 microgram pill in a  patch form’ but again, but remember this is sort of continuous release as  opposed to the usual peaks and valleys that you would see with an oral dose.   So direct comparability is really not possible.”  

:   “So but there is a…you can make a comparison.  You can compare them as well in terms of safety?” 

:   “If you look at the safety there are three large clinical trials  involving several thousand women.  Two  were comparative with oral contraceptives and one was just sort of a use of the  agent by itself.  From the  standpoint of efficacy the contraceptive failure rates are less than one  pregnancy per 100 women a year and that’s for both typical use, which is sort  of what, you know, is what reality is, as well as for method failure, that’s  where they use it correctly.  And in  fact, the numbers were so close together it clearly would suggest that the women  were adhering or complying with the correct use at a very high percentage of  time.  And in fact their self-report  done has suggested over 90% correctly used it each cycle.” 

:    “Yes, and what about the side-effects because we know that patches,  although they are much better than let’s say ten years ago, still can cause  some, well maybe fall off, or can cause some irritation.” 

:   “Well, for the patch itself, certainly from the standpoint of doing the  clinical trials, having subjects sort of complain of, you know, some skin  irritation that occurred in about 20% of subjects in the various clinical trials  but only 2.5 % of women decided well this was to the extent that they didn’t  want to continue.  From the  standpoint of adhesions there’s been over 70 000 cycles in the clinical trials  and it looks like complete detachment occurs in about 1.8%, partial detachment  in about 2.9%, something like that.  Overall  this does not appear to be affected by whether you’re in a cold climate or a  hot, warm, humid climate.  Also  studies have been done evaluating women who exercise, use saunas, all that sort  of thing and it appears that the patch adheres quite well.   So overall I think certainly it does very well from that perspective.” 

:   “So, these are kind of heavy-duty patches?” 

:   “Well, they’re heavy-duty in that they certainly deliver the goods so  to speak in terms of contraceptive efficacy and the side effect profile is very  similar to oral contraceptives but they actually are paper-thin.   When you look at this it looks like well, this is like a band-aid you  know one of those big square band-aids.  But  they are as thin as a piece of paper almost.   And so they are kind of interesting from that perspective to think that  you’ve got all this steroid in there that can deliver the levels that they do  in something as small as that.” 

:   “And other side effects, like spotting, like breast tenderness?” 

:   “Yes, the two side effects that, well, actually the one side effect  that’s a little different is breast tenderness.  This was seen in about 18-19% of women in the trials yet only  1% of women discontinued use because of breast tenderness.   Furthermore, when you sort of exam the data a little more extensively you  can see that most of the tenderness occurred only in the initial cycle and most  women described the discomfort as being mild to moderate.   Only about 14-15% felt that it was more significant than moderate  tenderness.  So it looks like it’s short-lived.  After a couple of cycles the degree of tenderness is no  different than say compared to OCs.  Bleeding,  break-through bleeding in the comparative trials was exactly the same between a,  for example, a triphasic level Norgestrel oral contraceptive and the patch.   There appears to be a little more spotting in the first cycle or so with  the patch compared to the oral contraceptive but again that’s sort of  short-lived.” 

:   “So women these days have a lot more choices for their device of  contraception than ten or 20 years ago.  For  which part, for which woman this kind of transdermal patch is the most  suitable?” 

:   “You sort of look at this and say, ‘Well, this must be one of those  sort of special sorts of methods of contraception’.   Well, in reality if you make women aware of its availability you very  quickly discover that a lot of the women, despite the birth control pill being  out there for several decades now, really it’s difficult for many women to  take this successfully, one pill each day without forgetting.   In fact in this country, the United States, after five months of the  patch being available, if the patch were an oral contraceptive it would be the  second most commonly prescribed birth control pill in this country.   So again, it certainly has taken off like crazy from the standpoint of  women accepting it and finding it to be a method that they can use successfully.   And I think the advantages, it’s weekly dosing.   They can look on their arm, they can look at their abdomen, know that  they haven’t forgotten anything.  And  it’s probably easier to do something on a Sunday once a week than it is to  remember ‘Did I take that pill or not’ because again, you may not have any  memory aids.” 

:   “Okay.  I think you’ve  convinced me that we have here a real good, new way for regulating the  contraception.  Thank you very  much.” 

“We just heard a presentation about one of the several new devices for contraception and you took part in a lot of research about this Transdermal Patches for contraception.

Transdermal Contraception: Contraception Patch. Interview with Ronald T. Burkman, MD


 A New Contraceptive Option:  
 A Focus on the  
 Transdermal Contraceptive System  

 Ronald T. Burkman, MD  
 Baystate Medical Center  
 Tufts University School of Medicine  






 Disclosure Declaration  

 •Grants and contracts  
 –NICHD, Ortho-McNeil Pharmaceutical, Inc.  
 •Honoraria and consultation fees  
 –Pharmacia Corp.  
 •Participation in company sponsored speakers’  
 bureau  
 –Ortho-McNeil, Wyeth, Berlex, Organon  






 U.S. Pregnancies:  
 Unintended vs. Intended  


 Unintended  49%:  
 Intended  51%
 Unintended births  22.5%  
 Elective abortions  26.5%  

Henshaw SK. Fam Plann Perspect. 1998;30:24-29.  





 Unintended Pregnancy: Consequence of  
 Ineffective or Non Contraceptive Use  

 •40% of unintended pregnancies  
 –attributable to 5% of sexually active women  
 (.3 million) who:  
 •do not desire pregnancy  
 •use no method of contraception  

 •60% of unintended pregnancies  
 –women using some form of birth control  
 –.1 million unintended pregnancies in OC users  


 Piccinino LJ, Mosher WD. Fam Plann Perspect 1998; 30:4-10,46.  





 Potential Medical Consequences  
 of Unintended Pregnancy  

 •Miscarriage  
 •Ectopic pregnancy  
 •Excessive vomiting  
 •Diabetes  
 •Hemorrhage  
 •Infection  
 •Pregnancy-induced hypertension  
 •Premature labor  
 •Need for a cesarean delivery  





 •Chronic diseases and medications  
 •Occupational exposures  
 •Sexually transmitted diseases (including HIV)  
 •Rubella immunization  
 •Folic acid  
 •Genetic history  
 •Nutrition and fitness  
 •Tobacco and alcohol use  
 •Psychological status  






 Maternal Health in the United States:  
 Magnitude of Problem  

 •Every year 6 million American women become pregnant;  
 half are unplanned  
 •Every day over 10,000 women give birth in the U.S.  
 •CDC estimates that every day:  
 –2-3 women die from pregnancy-related conditions  
 –2,100 women experience major pregnancy-related  
 complications before labor begins  
 –2,500 women have cesarean section delivery  
 –2,600 women experience major labor-related  
 complications  
 •Reducing unplanned pregnancy would significantly impact this  
 public health problem  






 Economic Consequences of  
 Unintended Pregnancy  

 Unintended pregnancies in women who  
 discontinue OCs account for ~20% of the  
 3.5 million annual unintended pregnancies,  
 incurring costs of nearly $2.6 billion.  

 Rosenberg, MJ et al. J Reprod Med 1995;40:355-60.  





 Trend in unintended pregnancy rate  
 (unintended pregnancies per 1,000 women 15-44)   
  

Source: Henshaw, Fam. Plan. Persp., 1998  






 Properties of Contraceptives  
 Desired by Women


 •Highly effective  
 •Prolonged duration of action  
 •Rapidly reversible  
 •Privacy of use  
 •Absence of amenorrhea  
 •Protection against STI  





 •Safe  
 •Effective  
 •Convenient  
 •Maintain regular bleeding episodes  
 •Rapidly reversible  






 Current Trends in Contraception  

 •Developing new delivery systems  
 •Increasing access to full range of options  
 •Emphasizing greater compliance  
 •Widening use of emergency contraception  
 •Recognizing non-contraceptive benefits  






 New Available Methods  
 of Contraception  


 E2C-MPA Injection 1 month  0.1 – 0.2  

 LNG-IUS  5 years  0.2  

 Etonogestrel-EE Vaginal  Ring  1 month  0.65  

 Norelgestromin-EE Patch  1 week  0.88  






 Improvements with Existing Delivery  Systems  

 •LNG IUS  
 –High efficacy  
 –Early spotting  
 –Reduction in menstrual  
 blood loss  
 –Low systemic levels of  
 LNG  
 –Releases 20 mcg / day  
 into the uterine cavity for  
 at least 5 years  
 –Requires clinician visit  
 for initiation and  
 discontinuation  

 •MPA/E2C  
 –High efficacy  
 –Regular monthly cycles  
 –1st injection within 5 days  
 of onset of menses  
 –Injection repeated every  
 28 (±5) days  
 –0.5 ml deep IM injection  
 –Deltoid, anterior thigh, or  
 gluteus maximus muscle  
 –Rapid return to fertility  







 New OC Formulation  
 25-µg EE/Tri-NGM  


 •Efficacious  
 •Tolerability comparable to a  
 20-.g EE OC  
 •Superior cycle control,  
 similar to the 35µg Tri-NGM  
 regimen OC  


 Hampton RM, et al. Comparison of a novel norgestimate/ethinyl estradiol oral contraceptive  
 (Ortho Tri-Cyclen® Lo) with the Oral Contraceptive Loestrin Fe 1/20 Contraception. 2001;63:289-95.  







 Historical Comparison* of  
 Cycle Control  


 *Based on pooled results from 2 separate clinical trials.  
 1Hampton RM, et al. Comparison of a novel norgestimate/ethinyl estradiol  oral contraceptive (Ortho Tri-Cyclen Lo)   with the Oral Contraceptive  Loestrin Fe 1/20 Contraception. 2001;63:289-95.  







 New Delivery System:  
 Vaginal Ring  

 Progestin: Etonogestrel: 120 µg/day  
 Estrogen: Ethinyl estradiol: 15 µg/day  
 •Worn for three out of four weeks  
 •Self insertion & removal  
 •Pregnancy rate 0.65 per 100 woman–years  

 Roumen FJ, et al. Hum Reprod. 2001;16(3):469-475.  




 •High efficacy  
 –Weight analysis  

 •Good cycle control  
 –Irregular bleeding was rare  
 (2.6% - 6.4% of evaluable cycles)  
 –Withdrawal bleeding occurred  
 (97.9% - 99.4% of evaluable cycles)  

 •Compliance with the regimen was met in 90.8% of  
 cycles  

 Roumen FJ, et al. Hum Reprod. 2001;16(3):469-475.  







 Clinical Overview:  
 Transdermal Contraceptive System  





 Application of the Transdermal  
 Contraceptive Patch on Abdomen  






 Patch Administration  

 •Simple administration schedule  
 –Apply weekly for 3 weeks  
 –Apply same day-of-the-week  
 –1 week patch-free  






 Estrogen and Progestin Delivery  

 •Patch contains 6.0 mg norelgestromin and 0.75  mg ethinyl estradiol  
 •Delivers continuous systemic doses of hormones  
 –150 µg norelgestromin (NGMN)  
 +  
 –20 µg ethinyl estradiol (EE)  
 •Direct comparisons to oral contraceptive delivery doses cannot be made  


 Abrams L, et al. FASEB J. 2000;14:A1479.  







 Review of Norgestimate in OCs

 •Most widely used progestin in US  
 •Long established safety profile  
 •Minimal androgenicity  
 •Minimal alteration of estrogen’s beneficial effect  
 on lipid profile  
 •Little or no effect on carbohydrate metabolism  
 •Good cycle control  

 Phillips A. Acta Obstet Gynecol Scand. 1990;152(suppl):21-24.  
 Phillips A. Steroids. 1990;55:373-375.  
 Corson SL. Clin Obstet Gynecol. 1995;38:841-848.  






 Patch Continuously Delivers NGMN  
 and EE Within Reference Ranges*  

 *Noncomparative data  
 Abrams L. et al., Contraception 2001;64:287-295.  





 Reference Range: Conclusions  

 •Contraceptive patch delivers mean steady- state concentrations of NGMN and EE  similar to 35mcg EE/NGM OC  
 •Patch delivers NGMN and EE within the  reference range  
 •Absorbed dose per day is 150µg NGMN  and 20µg EE  





 Dosing Reserve Beyond 7 Days:  
 Results for NGMN and EE  

 Abrams et al., Int J Gyn & Obstet 2000; vol. 70 (suppl 1): pg 78  





 Equivalence of Sites: NGMN Levels  

 Abrams L, et al..Clinical Pharm & Ther. 2000; 67(2):159  







 Equivalence of Sites: EE Levels  


 Abrams L, et al..Clinical Pharm & Ther. 2000; 67(2):159  



 A New Contraceptive Option:   A Focus on the   Transdermal Contraceptive System   Ronald T. Burkman, MD   Baystate Medical Center   Tufts University School of Medicine  

Author | Sandra Ann Carson, MD

Articles

A New Contraceptive Option: A Focus on the Transdermal Contraceptive System

Transdermal Contraception: Contraception Patch. Interview with Ronald T. Burkman, MD

A New Contraceptive Option: A Focus on the Transdermal Contraceptive System

A New Contraceptive Option: A Focus on the Transdermal Contraceptive System