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).
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.
_______________________________________________________