An Expert Interview With Mark Lebwohl, MD
Editor's Note:
On January 19, 2006, the US Food and Drug Administration (FDA) announced the approval of revisions to the safety labeling for the 2 topical calcineurin inhibitors, pimecrolimus cream (Elidel) and tacrolimus ointment (Protopic). The labeling will be updated with a boxed warning about a possible risk for lymphomas and cutaneous malignancies. The labeling will also emphasize that the drugs should be used as second-line therapy, and that their use in children under 2 years of age is not recommended. These labeling changes are in response to a February 2005 recommendation of the FDA's Pediatric Advisory Committee. This action has been controversial among dermatologists. Kristin Richardson, Editorial Director of Medscape Dermatology, interviewed Mark Lebwohl, MD, Chairman of the Department of Dermatology, The Mount Sinai School of Medicine (New York, NY), to discuss the implications of the FDA's actions.
Medscape: As you know, the FDA has announced the approval of updated labeling for topical pimecrolimus and tacrolimus. And as you also know, this has been a controversial decision, with many organizations, including the American Academy of Dermatology, registering their disagreement. What is your response to the decision?
Dr. Lebwohl: I think that the decision was made in a post-Vioxx atmosphere in which, from the FDA's point of view, the more you overwarn patients the better. In this case, because the alternatives to the topical immunomodulators are not nearly as safe as the topical immunomodulators, it's actually a decision that hurts patients. I also think that it's the first time that a black-box warning has been put on a drug not because of a side effect of the drug but because of the theoretical possibility of a side effect of the drug.
Medscape: Could you give us a review of what the data actually are? I know that one of the central issues is that the data of concern are based on systemic exposure, and with the topical immunomodulators we are talking about topical exposure.
Dr. Lebwohl: They didn't need to do any studies to let us know that squamous cell carcinoma and lymphoma are increased by oral tacrolimus because that's available in a drug called Prograf (tacrolimus capsules and injection), which is used in transplant patients. Transplant patients are immunosuppressed because of many drugs, including oral tacrolimus, and they [experience] an increase in lymphomas and squamous cell carcinomas. So theoretically, there's a reason to be concerned. And if topical pimecrolimus and tacrolimus were absorbed a lot, that certainly would be of concern. As it turns out, they're absorbed very little.
While I'm on that point I'll go off on a slight tangent. Oral tacrolimus causes hypertension and elevation of kidney function tests -- blood urea nitrogen and creatinine go up. In all of the studies of topical tacrolimus and topical pimecrolimus, the creatinine did not go up at all and the blood pressure did not go up at all. So you know that it's not absorbed enough to have a systemic effect.
We also did not see other signs of immunosuppression, which are more directly to the point. We did not see an increase in systemic infections in patients treated with topical pimecrolimus or tacrolimus. And -- most to the point -- we didn't see any increase in malignancies in patients treated with topical pimecrolimus or tacrolimus.
In fact, if you look at the Elidel (pimecrolimus) data, it's quite striking. [Editor's note: The data on the topical calcineurin inhibitors have been extensively reviewed in a paper by a task force convened by the American College of Allergy, Asthma, and Immunology and the American Academy of Allergy, Asthma and Immunology.] There were 23,000 patients studied in Elidel clinical trials; 19,000 received pimecrolimus and 4000 received placebo. There were 5 malignancies in the control group of 4000 patients. In the pimecrolimus group, where there were almost 5 times as many patients, there were only 2 malignancies. Now if the risk were even the same you would expect about 25 malignancies in the pimecrolimus group, but we only found 2.
In the clinical trials of Protopic (tacrolimus) more than 19,000 patients were treated, of whom 7600 were pediatric. There was no increase in systemic infections, no increase in malignancies, and no evidence of systemic immune impairment. The bottom line is that clearly there was no increase in malignancies. But that point was lost on the FDA.
Medscape: Could you discuss the animal studies?
Dr. Lebwohl: There are some animal data that I think we should look at. One is an oral rat and mouse study in which they basically fed tacrolimus and pimecrolimus to rodents at many times the maximum human exposure. And, for example, after feeding pimecrolimus to mice at 133 times the maximum human exposure, no lymphomas were seen. When they went to 258-340 times the maximum human exposure, a lymphoma was seen. So the bottom line is that you have to really overexpose these animals.
There was also a skin study in which they put the tacrolimus and the pimecrolimus in alcohol -- a vehicle that gets absorbed systemically much more than the cream and ointment that are currently on the market. So they actually got high systemic levels. And with pimecrolimus they needed 47 times the maximum human exposure to see a lymphoma. With tacrolimus they needed 26 times the maximum human exposure to see a lymphoma. So these are just off- the-chart exposures in order to get any sign that there's even the potential of malignancies.
With oral pimecrolimus there was a study in monkeys that was of concern. If you give massive quantities of pimecrolimus, the monkeys clearly get lymphomas. And if you give lesser amounts, they get lymphomas. (It's called immune-related lymphoproliferative disease, but basically it's the equivalent of a lymphoma or something headed to a lymphoma. It is virally induced lymphoma, and these monkeys commonly get lymphomas.) It turns out that at a dose of 15 mg/kg/d, which ends up being 35 times the maximum human exposure, 1 out of 8 monkeys got a lymphoma. And that has certainly been touted as a concern.
The other study that is of some concern is one in which tacrolimus was applied topically to mice in conjunction with 2 carcinogens: dimethyl benzanthracene, which is a tumor initiator, and TPA, which is a tumor promoter. It turns out that when you put on the dimethyl benzanthracene and TPA you get (if you look at the number of tumors in 20 weeks) about 0.1. So you need 10 mice to get 1 tumor with those 2 carcinogens applied. If you add tacrolimus to that you get 0.47, so that's almost 5 times as many tumors. And that certainly was of concern.
On the other hand, another study was published showing that, in fact, the topical calcineurin inhibitors block ultraviolet light and reduce DNA damage from ultraviolet light. So the argument was that the topical calcineurin inhibitors might actually be protective.
Medscape: Could you discuss the clinical studies that have followed patients treated with topical immunomodulators?
Dr. Lebwohl: There are many clinical studies looking at thousands of patients, including children, treated for years who showed no increase in malignancies. To provide some context, let's look at large databases of cancer incidence. In the Surveillance Epidemiology and End Results (SEER) database, 22 out of 100,000 people got lymphoma; 533 out of 100,000 in the Physician's Health Survey (PHS) database got nonmelanoma skin cancer. In 1.7 million tacrolimus-treated patients there were 11 lymphomas. And, as an aside, 6 of those were cutaneous T-cell lymphomas (CTCLs); the kind of lymphoma that you see with immunosuppression is a B-cell lymphoma. The reason this is interesting is that CTCL is often difficult to diagnose. In fact, often patients will be biopsied 10 times and on the 11th time they are diagnosed. And what is it misdiagnosed as? It's usually misdiagnosed as atopic dermatitis. So those patients probably had CTCL all along and were treated with tacrolimus. Actually, I don't think that the FDA panel realized that; they're not understanding that patients had CTCL that was being called atopic dermatitis all along.
Medscape: That's very interesting; I wasn't aware of that.
Dr. Lebwohl: But the bottom line is that even with the potential misdiagnosis, there was not an increase in malignancies.
Another interesting study was done by Dr. Mark Naylor. He followed 5125 atopic dermatitis patients treated with topical tacrolimus for up to 4 years. Thirteen adult patients developed nonmelanoma skin cancer. Of the 13, 12 were over the age of 40, and 1 patient was age 26. And that was 12 out of 1718 patient-years, which compares to 533 out of 100,000 -- it's almost identical to the PHS database. Ten of the 13 were diagnosed within 90 days of initiating application of tacrolimus, so they'd have to turn this into cancer pretty quickly for that to be the case. The point is that it's almost certainly not the case. Seven of the 13 skin cancers were not at the sites of application of the medication. Seven of the skin cancers were in areas of sun exposure where you'd expect skin cancers, and 7 of the patients had had previous nonmelanoma skin cancers. So these are patients at high risk. They also had other risk factors: They'd been on cyclosporine, had received phototherapy, so you take a very high-risk population and we still can't find an increase in the rate of malignancy.
Medscape: Are you concerned that the new labeling is going to limit treatment options for atopic dermatitis patients?
Dr. Lebwohl: Yes, of course.
Medscape: What are you saying to your patients about the new labeling?
Dr. Lebwohl: I tell them that if they look at the data, there's no evidence that the topical immunomodulators were associated with malignancy, and to my mind these drugs are clearly safer than steroids. And I will tell you that in appropriate patients I certainly use them as first-line therapy.
Medscape: Who do you think those appropriate patients are?
Dr. Lebwohl: I think if someone has a chronic, recurring condition on the face or intertriginous sites, for which it's actually a disservice to use a steroid, which we know causes side effects on the face and intertriginous skin. And topical immunomodulators don't.
Medscape: Some have suggested that the black-box warning is being used to address the concern about off-label prescriptions for children under 2 as first-line therapy.
Dr. Lebwohl: Well, you know, people on the panel were quite vocal about this, and the FDA undoubtedly used this to cut down on prescriptions of those agents, especially in the pediatric population. In doing so, I think that they've actually harmed that segment of the pediatric population.
Medscape: Could you elaborate a bit?
Dr. Lebwohl: What's safer -- topical steroids or topical immunomodulators? There's a very good paper published that looked at several steroids, and it turns out that absorption of pimecrolimus in human skin was lower than absorption of steroids by factors of 70 to 100.
I think that there's no question that steroids have more side effects, especially locally cutaneous side effects such as striae and atrophy. I actually routinely do use topical steroids in combination therapies for atopic dermatitis. When I have a patient who's not going to do well enough with one agent, which is a lot of atopic dermatitis patients, I'll put them on a combination of a topical corticosteroid and a topical immunomodulator, often for 2 weeks. And then I'll have them switch to using the steroids on weekends only, and then continue to use the topical calcineurin inhibitor every day.
Medscape: How are you now responding to the issue of long-term treatment?
Dr. Lebwohl: To my mind these patients have a chronic condition that is not going away. Often we try to stop the treatment but often we can't, and these patients are going to have a recurrence or they are going to continue with a low level of disease despite the combination of those 2 treatments. If you stop the agents in those patients, you know that the condition is going to come back. So my option then becomes systemic steroids or oral cyclosporine, or phototherapy, which is very difficult for many patients to do. There's no contest there. If I can treat them topically, I'm going to continue long-term topical calcineurin inhibitors.
Medscape: I think that pediatricians and primary care physicians are especially concerned and perhaps confused about the new labeling. What advice or direction would you give to them?
Dr. Lebwohl: I think that they don't know the data. And I would say that there are some (fortunately fewer) dermatologists who don't know the data. I recently was speaking at a meeting and I actually showed the data; a dermatologist got up and thanked me because she had been losing sleep because she's given these agents to so many patients and to her own children, and she was worried now that she had put them at risk for lymphoma. So they've really frightened people.
Medscape: So it seems as if the new labeling is not going to affect the way you treat your atopic dermatitis patients.
Dr. Lebwohl: Well, you know, it's been a little easier recently. I knew that this was coming, so for months when I gave out tacrolimus or pimecrolimus I would tell the patient, "You know there's going to be a warning put on this drug that it causes lymphoma or skin cancer; take my word -- you can ignore it. It's not based on real data."
Editor's Note:
On January 19, 2006, the US Food and Drug Administration (FDA) announced the approval of revisions to the safety labeling for the 2 topical calcineurin inhibitors, pimecrolimus cream (Elidel) and tacrolimus ointment (Protopic). The labeling will be updated with a boxed warning about a possible risk for lymphomas and cutaneous malignancies. The labeling will also emphasize that the drugs should be used as second-line therapy, and that their use in children under 2 years of age is not recommended. These labeling changes are in response to a February 2005 recommendation of the FDA's Pediatric Advisory Committee. This action has been controversial among dermatologists. Kristin Richardson, Editorial Director of Medscape Dermatology, interviewed Mark Lebwohl, MD, Chairman of the Department of Dermatology, The Mount Sinai School of Medicine (New York, NY), to discuss the implications of the FDA's actions.
Medscape: As you know, the FDA has announced the approval of updated labeling for topical pimecrolimus and tacrolimus. And as you also know, this has been a controversial decision, with many organizations, including the American Academy of Dermatology, registering their disagreement. What is your response to the decision?
Dr. Lebwohl: I think that the decision was made in a post-Vioxx atmosphere in which, from the FDA's point of view, the more you overwarn patients the better. In this case, because the alternatives to the topical immunomodulators are not nearly as safe as the topical immunomodulators, it's actually a decision that hurts patients. I also think that it's the first time that a black-box warning has been put on a drug not because of a side effect of the drug but because of the theoretical possibility of a side effect of the drug.
Medscape: Could you give us a review of what the data actually are? I know that one of the central issues is that the data of concern are based on systemic exposure, and with the topical immunomodulators we are talking about topical exposure.
Dr. Lebwohl: They didn't need to do any studies to let us know that squamous cell carcinoma and lymphoma are increased by oral tacrolimus because that's available in a drug called Prograf (tacrolimus capsules and injection), which is used in transplant patients. Transplant patients are immunosuppressed because of many drugs, including oral tacrolimus, and they [experience] an increase in lymphomas and squamous cell carcinomas. So theoretically, there's a reason to be concerned. And if topical pimecrolimus and tacrolimus were absorbed a lot, that certainly would be of concern. As it turns out, they're absorbed very little.
While I'm on that point I'll go off on a slight tangent. Oral tacrolimus causes hypertension and elevation of kidney function tests -- blood urea nitrogen and creatinine go up. In all of the studies of topical tacrolimus and topical pimecrolimus, the creatinine did not go up at all and the blood pressure did not go up at all. So you know that it's not absorbed enough to have a systemic effect.
We also did not see other signs of immunosuppression, which are more directly to the point. We did not see an increase in systemic infections in patients treated with topical pimecrolimus or tacrolimus. And -- most to the point -- we didn't see any increase in malignancies in patients treated with topical pimecrolimus or tacrolimus.
In fact, if you look at the Elidel (pimecrolimus) data, it's quite striking. [Editor's note: The data on the topical calcineurin inhibitors have been extensively reviewed in a paper by a task force convened by the American College of Allergy, Asthma, and Immunology and the American Academy of Allergy, Asthma and Immunology.] There were 23,000 patients studied in Elidel clinical trials; 19,000 received pimecrolimus and 4000 received placebo. There were 5 malignancies in the control group of 4000 patients. In the pimecrolimus group, where there were almost 5 times as many patients, there were only 2 malignancies. Now if the risk were even the same you would expect about 25 malignancies in the pimecrolimus group, but we only found 2.
In the clinical trials of Protopic (tacrolimus) more than 19,000 patients were treated, of whom 7600 were pediatric. There was no increase in systemic infections, no increase in malignancies, and no evidence of systemic immune impairment. The bottom line is that clearly there was no increase in malignancies. But that point was lost on the FDA.
Medscape: Could you discuss the animal studies?
Dr. Lebwohl: There are some animal data that I think we should look at. One is an oral rat and mouse study in which they basically fed tacrolimus and pimecrolimus to rodents at many times the maximum human exposure. And, for example, after feeding pimecrolimus to mice at 133 times the maximum human exposure, no lymphomas were seen. When they went to 258-340 times the maximum human exposure, a lymphoma was seen. So the bottom line is that you have to really overexpose these animals.
There was also a skin study in which they put the tacrolimus and the pimecrolimus in alcohol -- a vehicle that gets absorbed systemically much more than the cream and ointment that are currently on the market. So they actually got high systemic levels. And with pimecrolimus they needed 47 times the maximum human exposure to see a lymphoma. With tacrolimus they needed 26 times the maximum human exposure to see a lymphoma. So these are just off- the-chart exposures in order to get any sign that there's even the potential of malignancies.
With oral pimecrolimus there was a study in monkeys that was of concern. If you give massive quantities of pimecrolimus, the monkeys clearly get lymphomas. And if you give lesser amounts, they get lymphomas. (It's called immune-related lymphoproliferative disease, but basically it's the equivalent of a lymphoma or something headed to a lymphoma. It is virally induced lymphoma, and these monkeys commonly get lymphomas.) It turns out that at a dose of 15 mg/kg/d, which ends up being 35 times the maximum human exposure, 1 out of 8 monkeys got a lymphoma. And that has certainly been touted as a concern.
The other study that is of some concern is one in which tacrolimus was applied topically to mice in conjunction with 2 carcinogens: dimethyl benzanthracene, which is a tumor initiator, and TPA, which is a tumor promoter. It turns out that when you put on the dimethyl benzanthracene and TPA you get (if you look at the number of tumors in 20 weeks) about 0.1. So you need 10 mice to get 1 tumor with those 2 carcinogens applied. If you add tacrolimus to that you get 0.47, so that's almost 5 times as many tumors. And that certainly was of concern.
On the other hand, another study was published showing that, in fact, the topical calcineurin inhibitors block ultraviolet light and reduce DNA damage from ultraviolet light. So the argument was that the topical calcineurin inhibitors might actually be protective.
Medscape: Could you discuss the clinical studies that have followed patients treated with topical immunomodulators?
Dr. Lebwohl: There are many clinical studies looking at thousands of patients, including children, treated for years who showed no increase in malignancies. To provide some context, let's look at large databases of cancer incidence. In the Surveillance Epidemiology and End Results (SEER) database, 22 out of 100,000 people got lymphoma; 533 out of 100,000 in the Physician's Health Survey (PHS) database got nonmelanoma skin cancer. In 1.7 million tacrolimus-treated patients there were 11 lymphomas. And, as an aside, 6 of those were cutaneous T-cell lymphomas (CTCLs); the kind of lymphoma that you see with immunosuppression is a B-cell lymphoma. The reason this is interesting is that CTCL is often difficult to diagnose. In fact, often patients will be biopsied 10 times and on the 11th time they are diagnosed. And what is it misdiagnosed as? It's usually misdiagnosed as atopic dermatitis. So those patients probably had CTCL all along and were treated with tacrolimus. Actually, I don't think that the FDA panel realized that; they're not understanding that patients had CTCL that was being called atopic dermatitis all along.
Medscape: That's very interesting; I wasn't aware of that.
Dr. Lebwohl: But the bottom line is that even with the potential misdiagnosis, there was not an increase in malignancies.
Another interesting study was done by Dr. Mark Naylor. He followed 5125 atopic dermatitis patients treated with topical tacrolimus for up to 4 years. Thirteen adult patients developed nonmelanoma skin cancer. Of the 13, 12 were over the age of 40, and 1 patient was age 26. And that was 12 out of 1718 patient-years, which compares to 533 out of 100,000 -- it's almost identical to the PHS database. Ten of the 13 were diagnosed within 90 days of initiating application of tacrolimus, so they'd have to turn this into cancer pretty quickly for that to be the case. The point is that it's almost certainly not the case. Seven of the 13 skin cancers were not at the sites of application of the medication. Seven of the skin cancers were in areas of sun exposure where you'd expect skin cancers, and 7 of the patients had had previous nonmelanoma skin cancers. So these are patients at high risk. They also had other risk factors: They'd been on cyclosporine, had received phototherapy, so you take a very high-risk population and we still can't find an increase in the rate of malignancy.
Medscape: Are you concerned that the new labeling is going to limit treatment options for atopic dermatitis patients?
Dr. Lebwohl: Yes, of course.
Medscape: What are you saying to your patients about the new labeling?
Dr. Lebwohl: I tell them that if they look at the data, there's no evidence that the topical immunomodulators were associated with malignancy, and to my mind these drugs are clearly safer than steroids. And I will tell you that in appropriate patients I certainly use them as first-line therapy.
Medscape: Who do you think those appropriate patients are?
Dr. Lebwohl: I think if someone has a chronic, recurring condition on the face or intertriginous sites, for which it's actually a disservice to use a steroid, which we know causes side effects on the face and intertriginous skin. And topical immunomodulators don't.
Medscape: Some have suggested that the black-box warning is being used to address the concern about off-label prescriptions for children under 2 as first-line therapy.
Dr. Lebwohl: Well, you know, people on the panel were quite vocal about this, and the FDA undoubtedly used this to cut down on prescriptions of those agents, especially in the pediatric population. In doing so, I think that they've actually harmed that segment of the pediatric population.
Medscape: Could you elaborate a bit?
Dr. Lebwohl: What's safer -- topical steroids or topical immunomodulators? There's a very good paper published that looked at several steroids, and it turns out that absorption of pimecrolimus in human skin was lower than absorption of steroids by factors of 70 to 100.
I think that there's no question that steroids have more side effects, especially locally cutaneous side effects such as striae and atrophy. I actually routinely do use topical steroids in combination therapies for atopic dermatitis. When I have a patient who's not going to do well enough with one agent, which is a lot of atopic dermatitis patients, I'll put them on a combination of a topical corticosteroid and a topical immunomodulator, often for 2 weeks. And then I'll have them switch to using the steroids on weekends only, and then continue to use the topical calcineurin inhibitor every day.
Medscape: How are you now responding to the issue of long-term treatment?
Dr. Lebwohl: To my mind these patients have a chronic condition that is not going away. Often we try to stop the treatment but often we can't, and these patients are going to have a recurrence or they are going to continue with a low level of disease despite the combination of those 2 treatments. If you stop the agents in those patients, you know that the condition is going to come back. So my option then becomes systemic steroids or oral cyclosporine, or phototherapy, which is very difficult for many patients to do. There's no contest there. If I can treat them topically, I'm going to continue long-term topical calcineurin inhibitors.
Medscape: I think that pediatricians and primary care physicians are especially concerned and perhaps confused about the new labeling. What advice or direction would you give to them?
Dr. Lebwohl: I think that they don't know the data. And I would say that there are some (fortunately fewer) dermatologists who don't know the data. I recently was speaking at a meeting and I actually showed the data; a dermatologist got up and thanked me because she had been losing sleep because she's given these agents to so many patients and to her own children, and she was worried now that she had put them at risk for lymphoma. So they've really frightened people.
Medscape: So it seems as if the new labeling is not going to affect the way you treat your atopic dermatitis patients.
Dr. Lebwohl: Well, you know, it's been a little easier recently. I knew that this was coming, so for months when I gave out tacrolimus or pimecrolimus I would tell the patient, "You know there's going to be a warning put on this drug that it causes lymphoma or skin cancer; take my word -- you can ignore it. It's not based on real data."
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