December 25, 2008
10 min read

Black box warnings have hampered eczema therapy

The FDA issued black box warnings on two topical calcineurin inhibitors in 2006, saying they could cause cancer. Some argue the move was premature.

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In 2006, when the FDA instilled black box warnings on two topical calcineurin inhibitors, Protopic ointment (tacrolimus, Astellas Pharma) and Elidel cream (pimecrolimus, Novartis), it disappointed several medical groups, including the American Academy of Dermatology and the National Eczema Foundation. The warnings stated that the treatments were linked in postmarketing reports with cancer-related adverse events, including lymphoma and skin malignancies.

The result has been an uphill battle for some physicians in treating eczema and explaining the warnings to their patients.

Ilene L. Rothman, MD
Ilene L. Rothman, MD, is Physician in the Department of Dermatology at the Roswell Park Cancer Institute and Chief of Pediatric Dermatology at Women and Children’s Hospital of Buffalo, N.Y.

“As these groups feared, the black box warning has brought about a marked unwillingness among both physicians and patients to use this valuable addition to treatment options for atopic dermatitis, a difficult disorder,” Ilene L. Rothman, MD, physician in the department of dermatology at the Roswell Park Cancer Institute and chief of pediatric dermatology at Women and Children’s Hospital of Buffalo, N.Y., told HemOnc Today.

HemOnc Today spoke with leading researchers in the field and found that patients and physicians have become reluctant to use and prescribe these agents because of the black box warning.

“Whenever these agents are prescribed, we as physicians discuss the black box warning with the patient or parent not just to be sure they are adequately informed but also to put the information in perspective for them,” said Rothman. “This often involves a lengthy discussion, as the subject is complicated. Patients and parents also receive the warning again from the pharmacist and often again from other physicians, acquaintances, and on the Internet.”

“This has made responsible prescribing of these valuable agents difficult,” Rothman said.

With the FDA later advising that no causal relationship has been established between calcineurin inhibitors and cancer and that true data will not be available for another decade or so, did it act prematurely with the black box label? Lawsuits were filed last year against the makers of Elidel and Protopic claiming that not only did the creams cause cancer, but that the drug companies knew about the risk and failed to warn the public.

Has the black box label ultimately black-listed very valuable drugs?

Risk of cancer

This all began in 2005 when the FDA’s Pediatric Advisory Committee met to discuss animal studies that showed that three different species of animals developed cancer following exposure to these drugs applied topically or given by mouth, including mice, rats and a newer study of monkeys. These studies were conducted at doses higher than generally used by patients and the risk of cancer increased with increasing drug dose and duration, according to the FDA. It issued a public health advisory to inform health care providers and patients about the potential cancer risk based on information from the animal studies, case reports in a small number of patients and the science of how the drugs work.

DISCUSS IN OUR FORUM Do you think that Protopic ointment and Elidel cream should have been given black box warnings?

The AAD released a statement saying it was “very disappointed” with the FDA ruling, and that the science did not support the labeling. The AAD contended the cancer link was not proven and that the data showed these medications to be safe.

“I agree with the AAD,” said Matthew Keller, MD, faculty at Jefferson Medical College, Philadelphia. “These medicines have a more solid history of being safe than unsafe when used in normal clinical practice. As with all science there are more questions to answer, but in the face of so much uncertainty we should not be quick to remove a valuable drug based on scanty unscientific evidence.”

Rothman said that she believes the black box warnings were not warranted. “The FDA’s concern about possible systemic absorption of TCIs was partially fueled by animal data showing development of some lymphomas in mice,” Rothman said. “However, these lymphomas occurred after the mice were treated with massive doses of TCIs. Additionally, the skin of these mice is known to absorb topical agents much more readily than human skin. Studies with humans have found negligible systemic absorption of TCIs except in some rare disorders with unusually poor epidermal barrier function.”

The FDA said in the health advisory that it may take human studies of 10 years or longer to determine if use of Elidel or Protopic is linked to cancer, and that the risk is uncertain.

“The FDA is right on one point: we do need longer data points to further clarify the issues raised by the case reports and animal studies,” Keller said.

Philip D. Leming, MD, medical director of the department of cancer research of The Christ Hospital, Cincinnati, Ohio, said that the calcineurin inhibitors, when given systemically in animals and humans, suppress the T-cell system and are associated with increased incidence of malignancies in such immune suppressed patients.

“The warnings are being extrapolated from this data and not clinical trials topically used where the systemic effect is insignificant,” Leming said. “I feel these warnings are more medico-legal driven than evidence-driven.”

Black box labeling

Robin P. Gehris, MD
Robin P. Gehris

Months after the health advisory the FDA updated the boxed warning with a medication guide and also clarified that, to date, “no causal relationship has been established between calcineurin inhibitors and cancer.” The agency also noted the drugs are recommended for use as second-line treatment.

“The actual wording of the warning itself reflects the weak basis for a black box warning,” Rothman said.

It begs the question: Why did the FDA do it? At the time the FDA said it was merely taking steps to ensure that health care providers and patients were made aware of the possible long-term risks of these products so that they would be used appropriately.

A point brought up by many dermatologists interviewed for this article is that Elidel and Protopic were developed at a time when the FDA’s standards for topical medication approval were at an all-time stringent high, so these medications were placed through rigorous testing requirements, perhaps more rigorous than any of the topical steroids that have been mainstays of treatment in the past.

Robin P. Gehris, MD, chief of pediatric dermatologic surgery at Children’s Hospital of Pittsburgh, said one of these tests included taking the active agents in these creams, pimecrolimus for Elidel and tacrolimus for Protopic, and administering them in large oral doses (far greater than would ever be administered to a human) to lab monkeys infected with lymphocryptovirus, a virus similar to Epstein Barr virus that places them at risk for immunosuppression-related lymphomas.

“At very high oral doses, a percentage of these virally infected monkeys developed an immunosupression-related lymphoma that behaved as one would expect such a lymphoma to behave — it regressed spontaneously when the drug was withdrawn and recurred when the high-dose oral drug was reinstated,” Gehris said.

Gehris pointed out that no such cases have ever been described with the topical use of these medications either in children or adults. “The black-box warnings placed on Elidel and Protopic are based on this oral animal data and are not relevant in our clinical practice,” Gehris said.

FAST FACTS: Issues at Hand

Alan Menter, MD, chief of dermatology at Baylor University Medical Center, Dallas, agreed that there is no evidence to support a risk if used topically only. He noted that Baylor has a long record of safely using these products in adults and children.

“The FDA is in a state of extreme concern for safety and is taking very extreme views that are not justified by science or usage,” Menter said.

“It has therefore created undue concern among parents and patients about the safety of these creams. In reality, I purposefully use these creams as a safer alternative to topical steroid use,” Gehris said.

Precautionary principle

Robert Dellavalle, MD, PhD, MSPH, chief of dermatology service at the Denver VA Hospital, said he agreed it was better for the FDA to be cautious about the possible risks with the TCIs, despite the fact that it could possibly inhibit people from taking the medications who need them.

“As a public health practitioner as well as a dermatologist, I believe, like Osler, that it is important to never underestimate the power of medications and to practice the precautionary principle — that harm does not need to be undeniably proven in order to be avoided,” Dellavalle said.

Although many may argue animal testing may not have been a stable indicator, in its defense, by December 2004 the FDA had received 19 cases of post-marketing case reports linking Protopic with cancer-related adverse events. According to the administration, three cases occurred in children up to 16 years of age and 16 cases occurred in adults. Two deaths in adults were reported related to complications of the cancers, eight hospitalizations and two hospitalizations in pediatric patients, according to the FDA.

The 19 postmarketing cases included nine lymphomas, 10 cutaneous tumors, of which seven occurred at the site of Protopic application, as well as cases of squamous cell carcinoma, cutaneous sarcoma, malignant melanoma and other tumor types. The median time until diagnosis after initiation of treatment with Protopic was 150 days, with a range between 21 days and 790 days. Six cases also reported lymphadenopathy. Two cases reported pre-existing serious conditions, and four cases reported a recurrence or aggravation of a pre-existing malignancy. Three additional cases were confounded by other possible risk factors, including environmental exposure, or pre-existing conditions that may have been premalignant.

“Measurements in the human studies showed the vast majority, more than 99% of patients, achieved nearly undetectable blood levels that were and still are believed to have no biologic activity,” Keller said. “Also, some have cited the rates of lymphoma, non-melanoma and melanoma skin cancer at or below the untreated population, furthering the point that the case reports may be erroneous.”

Although it may be too early for any data from large prospective studies on cancer risk from TCIs to substantially prove that there may in fact be cause for concern, there have been several large retrospective studies looking at experience from the millions of patients who have now been treated with TCIs, according to Rothman.

“These have not shown any increased risk of lymphoma or skin cancer,” Rothman said. “In fact, there are some data showing a lower rate of lymphoma in the TCI-treated groups.”

Balancing the scales

Many of the dermatologists interviewed by HemOnc Today described the uphill battle they are now facing in using these medications. Tara L. Kaufmann, MD, director of clinical and cosmetic dermatology at Stony Brook University Medical Center, said that physicians need to counter the negative attention the black box labeling has garnered by counseling patients and their parents about the facts behind the FDA warning.

“It is obvious that placing a black box warning severely inhibits prescribing habits of a medication,” Kaufmann said. “I do think that many doctors do not want to spend the extra five to 10 minutes it requires to counsel a patient on a warning and therefore some patients who could benefit from these medications never receive an opportunity to try them.”

“In my experience, [Elidel and Protopic] play a crucial role in maintenance treatment of these common skin disorders in that they are not able to cause any of the untoward side effects that topical steroids do, such as glaucoma, stretch marks, atrophy or thinning of the skin or dyspigmentation,” Gehris said.

Sidney Herszenson, MD
Sidney Herszenson

Sidney Herszenson, MD, dermatologist, Wheaton Franciscan Medical Group, Brookfield, Wis., said that it is difficult to care for patients with all of the side effects, especially the black boxed ones.

“It would appear that the FDA overreacted in the labeling of these drugs,” Herszenson said. “Some studies show links with lymphomas happening without any of these inhibitors. There hasn’t been any increased risk with patients with the alpha inhibitors. Further studies reveal that there’s really minimal to no absorption chemically when these drugs are applied to the skin,” Herszenson said.

“The FDA has to do what they feel is in the best interest for society as a whole,” Keller added. “We treat patients and must do what is best for our patients. If a black box warning keeps a drug on the market and lets me treat my patients appropriately until further evidence sways us one way or another than so be it,” Keller said.

Mary Lien, MD, a dermatologist at the H. Lee Moffitt Cancer Center, Tampa, Fla., said that unfortunately sometimes patients do rely on hearsay, which may be exaggerated.

“An educated patient should weigh all the available data put forth by the FDA as well as the professional recommendations of his/her clinician in order to make the best informed decision that is customized to his/her physical state,” Lien said.

“The FDA adheres to its own set of guidelines regarding evaluating the efficacy and safety profiles of newly developed medications,” Lien said. “Clinicians who use the medications on a large scale may feel more comfortable with the safety profiles based on their own personal experiences.”

Damage caused

Mary Lien, MD
Mary Lien

Leming said the fear of legal repercussions in this country has nearly paralyzed common sense in many aspects of society, one of which is health care.

“There is a role for reasonable safety recommendations and guidelines, but there are no totally safe, guaranteed treatments or medications,” Leming said. “There are always risks in everything. The skill is in wording information to inform and not induce fear unless the degree of risk and fear is warranted.”

“The FDA has a responsibility to protect and inform, but in a reasonable and appropriate fashion,” Leming continued. “The black box warnings are useful if the risk is severe or life-threatening and supported by clinical studies. Otherwise it opens the door for legal ramifications and inappropriate fears and avoidance of use,” Leming concluded.

As far as the damage caused by the black box labeling, it’s still hard to tell for most physicians.

“No one can say what effect it had in a single patient retrospectively,” Keller said of the labeling. “We treat patients, not statistics,” Keller said.

“If I have a patient who is reluctant to use any medicine, I do not force them to do so. I simply give them the facts and my opinion allowing them to make an informed decision. Just because a medicine is believed to be safe does not mean a patient that does not need to use it should. For instance, treating highly recalcitrant eczema for maintenance is a good place for Elidel/Protopic. Treating rosacea that could be controlled by other means for 25 to 30 years may not be. Though both patients probably have negligible risk from my point of view, they don’t both necessitate the therapy,” Keller said.

Oncologists should first educate themselves about the availability of these agents in dermatology and then discuss the reason for the warnings with the patient and let them decide, Leming said. Also, the risks of long-term corticosteroids should also be discussed as well. None of the treatments are completely without risk, he said.

“It is the risk/benefit ratio that we as oncologists have to deal with and educate patients on all the time. This is no different, except the risks associated with these agents are not in the same category of risks we deal with in chemotherapy treatments,” Leming said. – by Angelo Milone

Should Elidel and Protopic have been given a black box warning? How should physicians consider use of TCIs?

For more information:

  • Breuer K, Werfel T, Kapp A. Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis. Am J Clin Dermatol. 2005; 6: 65-77.
  • Draelos Z, Nayak A, Pariser D. Pharmacokinetics of topical calcineurin inhibitors in adult atopic dermatitis: A randomized, investigator-blind comparison. Am J Clin Dermatol. 53: 602-609.