The FDA has updated the labelingfor the Ortho Evra Patch to warn users that the patch may have a higher risk of blood clots than other lower dose hormonal contraceptives.This is the second major labeling change since the patch was approved in 2001. The first change came in 2005, when it was found that the patch exposed women to increased levels of estrogen compared to low dose pills. This latest labeling change includes data from two recent studies that found a two-fold increase in thrombo-embolic events associated with the patch (as well as a third study that found no increased risk).
Although a bit late, I believe that the FDA is doing the right thing. Women who use the patch need to be informed that they are taking a higher dose estrogen product, and that higher doses may cause more clots.
It’s called informed choice.
A Little Background
In retrospect, I was not surprised to find out in 2005 that the patch has higher estrogen exposure than most pills. Breast tenderness was reported in the clinical trials in around a fifth of patch users, compared with less than 10% of pill users. And I had seen the same complaints from my patients who were using the patch.
In fact, shortly after the patch came on the market, I had begun to wonder about the estrogen levels and how they compared to the pill. Unfortunately, neither the package insert nor the contraceptive literature was helpful – no one source had comparative data. I remember asking the Ortho rep if he could tell me how the estrogen dose in the patch compared with a 35 microgram pill. The answer was something like “It’s like comparing apples and oranges. The trans-dermal dose has a different metabolism, so you can’t compare the dose itself.” Which is technically true.
But what you can compare is total estrogen exposure, something pharmacokinetics experts call “the area under the curve” or AUC. This kind of comparison was published in 2005 in a study comparing the patch to the vaginal contraceptive ring and a 30 ug (standard dose) pill.
Lo and behold, the AUC for patch users was 3.4 times that of ring users and 60% higher than in pill users! Now all that breast tenderness made sense. (This was the kind of data that prompted the Ortho Evra label change in 2005.)
Here was my thinking, simplistic though it may be. If EE levels are 60% higher on the patch than the 30 ug pill, doesn’t that mean the patch is equivalent to a 48 ug pill? And didn’t we long ago stop prescribing 50 ug pills because the clot risk was too high? So if I wasn’t routinely offering my patients the 50 ug pill as a first line method, why would I routinely prescribe the patch as a first line method?
Just because the patch isn’t first line, does not mean it has no place in our birth control armamentarium.
What kind of women might want to use the patch? Well, some women take other meds that interfere with the effectiveness of birth control pills. Topamax is the most common such drug. For these women, the higher estrogen levels in the patch may be enough to give them the protection they need against pregnancy.
Another candidate for the patch is the woman who can’t remember to take a pill and is unable to use a barrier or IUD. Such a woman will often be willing to accept the higher estrogen dose in return for protection against pregnancy. This is not an unreasonable trade-off if you have had an unplanned pregnancy due to missed pills. However, is you want ease of use and compliance, you could also use the Nuva Ring, which comes at a much lower dose (but the clotting risks have not been compared). So that’s your choice.
The CME Response
I am getting a bit perturbed with all the posturing and spinning about the patch out there in CME land. All the thought leaders with conflict disclosure lists longer than my CV, who are weighing in on the clot data. Arguing that the studies are not conclusive, that one study used medical chart data and the other insurance claims data, etc., etc. Some are insinuating that the media is over-hyping the risks of the Patch, despite what seems to me to be quite responsible reporting on this issue.
C’mon guys. Most of you have spent the last 4 decades convincing us all that pills are safer than they were years ago, largely because the estrogen dose is lower. Don’t ask us to ignore those risks now.
More questions
I keep asking myself – Could Ortho and the FDA not have known this data? Didn’t anyone ask how the patch and the pill compare? If they were seeing breast tenderness and nausea at a higher than expected rate in patch vs. pill users in the clinical trial, didn’t they wonder what estrogen levels were?
So I went back and read the initial FDA review of the patch to see what sort of data was presented in this regard. Turns out the reviewers did note that weekly estrogen exposure was higher in patch than pill users, and directly related this data to the two pulmonary emboli reported in clinical trials.
There were two Pulmonary Emboli reported during the trial in patch users, one of which Ortho tried to discount since there was a protocol violation. The FDA’s reviewer disagreed and insisted that both cases be counted. The reviewer also recommended that the package insert reflect a concern that the patch has an increased risk for venous thromboembolism. In the end, the package insert merely stated that “it is unknown if the risk of venous thromboembolism with Ortho Evra is different than that for oral contraceptive users.”
Now what the FDA and Ortho could have done was to approve the patch as a niche method with known higher estrogen levels which, on balance, could be seen as an acceptable price to pay for the ease of use and compliance. Instead it was approved and marketed it as a first line method for any woman, with no discussion as to how estrogen levels might compare to other products already available out there. And I think that was just wrong.
Compare this to how Ortho advertizes their pill Ortho Tricyclen lo – “Do you want a high level of effectiveness and a low level of hormones?” it asks us on their web site. As if any of these methods have low hormones – they all work because their hormone levels are supra-physiological. But Ortho’s marketing folks know that women believe lower hormone levels are better. Why? Because that’s what we’ve been telling them for years!
The right way to label the patch
So, to make a very long story short, it took us 7 years to get here, but the FDA prodcut labeling for Ortho Evra is finally appropriate.
And Ortho’s website now states, “The patch is a not for everyone”. And that’s right. The patch is a niche method. It absolutely should remain on the market for those women who for whatever reason, can’t or don’t want other methods and are willing to accept a slightly higher clot risk in return for the benefit of effective contraception. But it’s not for everyone.
So, what is the risk?
Actually, despite everything I’ve just said, the risk for getting a blood clot on either the pill or the patch is quite low. How low? Well, that depends on what you think the background risk for DVT is in the general female population. For argument’s sake, let’s say that risk is 5 per 100,000 women per year. (A commonly quoted number, represented by that little red dot at the bottom right of the grid of 10,000 women).
The risk with oral contraceptives would be about 20 per 100,000 and the risk with the patch about 40 per 100,000 women per year.
Now, compare that to the risk of a DVT in pregnancy – about 16 per 10,000.
These are very low risks, aren’t they?
But multiply them by the millions of women using a method for decades of their life, and you can see that the differences in risk can lead to significant increases in population rates of DVT. And, if you had a choice between two birth control methods that were equally effective for you, you might want to choose the one with a lower risk. On the other hand, if the method with the higher risk was more effective for you, you might be willing to accept the increased risk in return for that efficacy.
As I said, it’s all about informed choice.
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Thank you for keeping it sane.
I love the way the dot charts help make the odds so visual.
Thanks for the explanation!
Here’s a question that might be interesting? How does a woman know when it’s time to stop using the pill (say, she’s really happy with the pill, but into middle age)?
Bardiac –
The only way to know is to stop the pills and see if one is menopausal. Checking hormones may be an indicator, but doesn;t always predict whether things will stay that way.
I usually have my patients wait till they are 50 or 51 to see where they are. The average age of menopause is 51.5 years.
Thanks for the question. I’m enjoying your visuals from the Far East.
Thanks for the great explanation of the patch debate. Ortho reps lost their credibility with me when they claimed at a med school reproductive health lecture that no one had ever had a skin reaction to the patch or adhesive it used. No one ever?? Seems unlikely.
I love the dot charts. Did you create them yourself? How can I get some?
Kristie –
This whole patch episode was so sad for me – I’ve lost faith on so many fronts, but I think am wiser and a better doctor for it.
Dr Val-
Thanks, I made them myself. They are extremely helpful. I even used them today in conveying risk to a patient regarding her birth control pills.
Feel free to copy them. They are just JPEG files.
TBTAM – Thanks for the great explanation. You have a great knack for boiling this stuff down to easily digestible tasty morsels. 🙂
I am one of those little dots (pulmonary embolism on oral contraceptives). The risk is never miniscule when it happens to you!
Kacee- You are absolutely right, The risk for you was 100%, wasn’t it?
Then again, millions and millions fo women use oral contrceptives and never get a clot.
One of these days we’ll be able to identify just who those little dots are, and identify them before they take a medication that for them is risky, without denying the medciation to all the others who may never have a problem. It’s evolving quicker than you realize.
We already have testing that will tell us which women carry a gene that predisposes them to clotting from pills (and from pregnancy). Problem is the test is too expensive for widespread screening, but I do find it valuable in women with a family history of clotting.
Glad you’re ok.
when my OB-GYN and I decided the ring was my best choice, my insurance company insisted that the patch was the proper substitute and turned down my first request.
Fortunately my charts are full of allergy history and I refused because i know I can not tolerate any adhesive longer than about 24 hours.
Thank goodness they then agreed to pay for rings. Now I am even happier with the end situation, having read this.
Found your blog cuz of the food, just today. Very glad I kept reading.
K, I’m a little late here (computer crash). Call me crazy, but WHY doesn’t Ortho simply *lower the micrograms* of the patch? Clearly, more hormone is utilized, through the avoidance of first-pass. Does it not make sense to decrease the medication dose???? It’s an important method, mostly for teens, and I don’t want to lose it. As is, I won’t Rx it. And that’s a shame.
Maribeth – I know – I feel the same way. But even if they are going for a lower dose, it’s years away.
I rx it, but only after informing my patients of the differentioal in estrogen dose. For most of them, the differece isn’t worth it, but for some, it is, and I am willing to prescribe it for them, The risks are low, after all.
I didn’t get into the nuances of the data, but the background clot risk in some of the studies for pills was extremely low, so that the relative risk for the patch still ended up with a low risk.
I, too, developed DVT as well massive major PEs as a result of oral contraceptives. However, in my case I was also on Prednisone and the consensus of 3 out of 5 doctors is that it was the combination of the two drugs given the timing of the event. I had also been on a 8 ½ hour flight one month earlier. My question is, what percentage of DVT/ PE from BCP occur in women without an underlying clotting disorder or predisposition?
AMG-
Not sure we have that data, since not everyone is screened for these underlying problems in the studies that have been done.
I can tell you I recently screened a new patient of mine who told me she had had a clot on the patch 5 years ago after a series of long plane flights- turns out she has prtein S deficiency, something that it is important for her to know, and also for her family memebrs to know, since this is genetically transmitted.
At this time, it is not cost effiicnt to screen everyone for underlying genetic disorders before using oral contraeptives or the patch. I do screen in those with a fmaily history, but FH does not always find everyone.
Thansk for reading.
It’s interesting looking at the plasma chart. The system was obviously designed to maintain steadystate (SS) plasma levels of the EE2 significantly below peak levels for the 30 mcg pill. I wonder if they attributed the higher blood clot frequency with peak versus SS levels. Was this data even available to them when the system was in initial clinical trials? Patches that deliver two drugs often use an enhancer to increase the delivery on the progestone compound (norelgestromin, I think in this case) due to its inherent lower transport rate thru the viable epidermus. EE2 compounds can be delivered in the required dosages with very little, if any, enhancer required. This system probably has an EE2 concentration below saturation in the patch formuatlion and the norelgestromin is probably in excess of saturation to maximize delivery rate with the smallest patch size. To reduce the EE2 delviery (and thus the plasma concentrations) the patch size could be reduced, say by half. Total drug delivered and patch are directly related. However the norelgestromin would also be reduced by half. The other option would be to reduce the EE2 concentration by half. Other material changes might be required depending upon the patch formulation complexity. I wonder if they looked at alternate formulations exploring this option during product development? Regardless, I’m certain that they do not want to address these significant product changes at this stage of the product life.
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