NEA-Funded Research Report Offers Independent Guidance
regarding the Use of Two Popular Eczema Drugs

A report released in October 2005 by the National Eczema Association (NEA) offers guidance to both patients and physicians regarding the use of two common skin care medications that have been the subject of public health advisories by the Food and Drug Administration (FDA). In the NEA report, physicians from Brigham and Women’s Hospital (BWH) in Boston, Massachusetts, provide an independent review of the clinical benefits and potential cancer risks associated with the drugs Elidel (pimecrolimus) and Protopic (tacrolimus).

Protopic was initially approved by the FDA in December 2000 and Elidel was approved in December 2001. But last February, the FDA’s Pediatic Advisory Committee voted to recommend that the labels for these two prescription eczema drugs include a black box warning that they may increase the risk of cancer, especially in children. The following month the FDA issued a formal public health advisory and said that possible labeling changes, including black box warnings, would be reviewed and studied by the FDA staff. On January 20^th, the U.S. Food and Drug Administration approved a black warning and a medication guide.

In the wake of the previous FDA’s actions, NEA determined to fund an independent study of current evidence regarding the safety of Elidel and Protopic, and it issued a call for proposals last spring. A peer review committee selected a proposal submitted by two physicians at Brigham and Women’s Hospital—dermatologist Abrar A. Qureshi, MD, MPH, and pharmacoepidemiologist Michael Fischer, MD, MS. Their application was excellent, their caliber unsurpassed, and they had no funding from and no association with the companies that make these drugs.

In their finished report, Drs. Qureshi and Fischer highlight several larger trends and challenges facing the pharmaceutical industry and its governing body:

• The limitations of drug safety information from pre-marketing trials.
• The inability of black box labels to adequately instruct physicians toward better prescribing.
• Aggressive prescription drug marketing that may encourage off-label use
• Lack of post-marketing safety data; when trials are not initiated promptly, valuable information about potential side effects is lost.

“When news of the proposed safety warnings for Elidel and Protopic were released, calls from concerned patients flooded dermatology offices like ours because there was confusion and questions about whether or not patients should discontinue use,” said Qureshi. “NEA recognized there was a void in valuable information that both patients and providers needed to interpret the FDA’s safety concerns. Our report aims to fill that gap by providing a balanced review of the clinical benefits and potential risks associated with these two medications. It also shines the light on a larger issue facing industry and the FDA: black labels are not enough. We need more instructional information when trying to interpret safety warnings, and more importantly, better long-term follow-up of a drug’s safety profile.”

The report offers the following information and guidance to patients and doctors regarding the use of Elidel and Protopic:

1. Topical pimecrolimus (Elidel) and tacrolimus (Protopic) are two new topical calcineurin inhibitors that can be used for the treatment of atopic dermatitis.

2. The advantage of these calcineurin inhibitors over topical steroids is that they do not cause skin thinning or ocular side effects, making them especially useful for sites such as the face where skin thinning may develop quickly.

3. Short-term data on systemic side effects for tacrolimus and pimecrolimus are reassuring; systemic absorption is low in majority of patients, and cancer takes years to develop. Long-term safety data are incomplete.

4. Both agents have been used “off-label” extensively—that is, they have been used on patients under 2 years old—and both agents have been portrayed as being safe for long-term use during marketing.

5. Recent concerns triggered by sporadic spontaneous case reports of skin cancers in adults and lymphomas in children have caused the FDA to consider requiring a “black box” warning to the label for each of these agents.

6. Sporadic case reports are an unreliable source to infer causation; at best they can serve as a signal for a possible association. Long-term data from Phase IV studies is not available and 4 to 5 years of potential data have been lost because these studies were not initiated promptly.

7. Animal studies suggest that when used at very high systemic (not topical) doses, both agents may be associated with the development of skin cancers and lymphomas.

8. Phase IV post-marketing surveillance studies are probably the best way to gather the data to answer the question of whether topical tacrolimus and pimecrolimus may cause cancer.

9. Two such comprehensive studies have just recently been set up by pharmaceutical companies who manufacture topical tacrolimus and pimecrolimus.

10. It will take another 5 to 10 years before enough data is available from such studies to help understand a possible association, if any, between the use of topical tacrolimus and pimecrolimus and the occurrence of cancer.

11. The possible association between topical tacrolimus and pimecrolimus and cancer therefore remains unclear and physicians have been urged by the FDA to only use these agents within strict parameters in order to maximize benefits for those who need it and to limit unnecessary use.

12. Physicians and patients need to work closely together to ensure clinical follow-up and compliance with therapy.

Organizations such as NEA and the FDA, scientists and clinicians across the country, and the companies that make tacrolimus and pimecrolimus are all trying to provide information on the safety and efficacy of these drugs. The overall message may be confusing to individuals suffering with atopic dermatitis and to their physicians or other providers. This report is a step forward in better understanding the issue of tacrolimus and pimecrolimus safety in the context of cancer occurrence.

The primary message of this report is as follows:

There is concern that tacrolimus and pimecrolimus may be associated with cancer occurrence. These drugs have not been proven to be completely safe at this point in time, but formal research studies to determine their safety have now been initiated. It will take at least 5 to 10 years before we have more information. Until then, the drugs may be used in certain cases as an alternative to or in combination with topical steroids, but their use should be carefully monitored and patients should be followed closely. The efficacy of these calcineurin inhibitors compared to topical steroids should help guide physicians to pick the drug most appropriate for their patients. The use of pimecrolimus and tacrolimus should be restricted to patients who are at least 2 years old. For physicians, there is no better guidance than judicious clinical judgment. For those suffering with atopic dermatitis, there is no better substitute than good compliance with the therapeutic plan and follow-up with their physician.

A newly revised full report will be published in a future issue of the Archives of Dermatology.

---

Statement of the National Eczema Association(NEA) regarding the Food and Drug Administration’s new warning label and medication guide for the class of drugs known as calcineurin inhibitors.  (January 23, 2006)

The National Eczema Association (NEA) is pleased to report that new guidelines from the Food and Drug Administration (FDA) on the use of the class of drugs known as calcineurin inhibitors confirm information that the NEA has previously communicated to eczema patients on their safe use.

The FDA guidelines echo the advice offered to patients and physicians this past fall by the researchers that the NEA commissioned to complete an objective and independent review of all evidence regarding the effectiveness and possible side effects of topical calcineurin inhibitors. Like those researchers, the FDA has concluded—and the new FDA-mandated warning label states—that to date no causal relationship has been established between calcineurin inhibitors and cancer.

This FDA statement should relieve some concern on the part of patients who use these medications according to the label’s instructions and in consultation with their physicians and obtain significant benefit from their use.

The researchers funded by the NEA, Drs. Abrar A. Qureshi and Michael Adam Fischer, who are instructors at Harvard Medical School and physicians at Brigham and Women’s Hospital in Boston and who have never received any type of support from the manufacturers of calcineurin inhibitors, found that long-term safety studies of these drugs are presently incomplete. They have estimated that it will take another 5 to 10 years before enough data is available to understand any possible association between the topical use of tacrolimus and pimecrolimus and the occurrence of cancer.

Physicians and patients need to work closely together to ensure that these drugs are used as directed and the necessary clinical follow-up is done.

The NEA will continue to support studies to determine the long-term safety of all forms of treatment options, and to share the best evidence with patients, physicians, and the public as soon as it is available.

In the interests of full disclosure, it should be noted that the NEA has received funding from the manufacturers of Protopic® (tacrolimus) ointment and Elidel® (pimecrolimus) cream, both of which are included in this class of drugs.

---

The National Eczema Association’s Statement of March 10, 2005 Concerning the Use of Protopic and Elidel (Topical Calcineurin Inhibitors)

The information expressed in this statement does not dictate an exclusive treatment course and is not intended as medical advice. Persons with questions regarding specific symptoms and treatments should consult a professional health care provider who has appropriate training and experience.

On February 15, 2005, the Food and Drug Administration’s Pediatric Advisory Committee met to discuss the evaluation, labeling, risk communication, and dissemination of information regarding the potential cancer risk among pediatric patients treated for atopic dermatitis with topical dermatological immunosupressants (more specifically, pimecrolimus, which is marketed under the name Elidel®, and tacrolimus, which is marketed as Protopic®). On March 10, 2005, the Food and Drug Administration (FDA) issued a Public Health Advisory informing health care providers of safety concerns associated with the use of these two eczema drugs.

There are risks and benefits associated with the use of all drugs, and pimecrolimus and tacrolimus are no exception. Tacrolimus and pimecrolimus are often prescribed in a topical form for use by eczema patients two years of age and older.

At a meeting on February 20, the NEASE Scientific Advisory Committee decided that NEASE should support outside independent studies of the risks and benefits of these two drugs. The Committee also wants NEASE to conduct an independent study of calcineurin inhibitors on UV effects on skin cells in vivo. The committee recommends that all dermatology, pediatric, and allergy patients with new diagnoses of eczema be studied to determine the efficacy and long-term effects of various treatments. Requests for proposals to major university centers will be released shortly.

Currently, it appears that tacrolimus and pimecrolimus are reasonably safe when prescribed in the manner approved by the FDA. But we don’t know what danger may arise when utilization deviates from that which is approved, especially on children under two years of age where the surface to volume ratio is much greater than in older children and in adults. Any decision to use these medications on the skin of infants with a disrupted barrier must weigh the potential and mostly unproved risks of treatment versus the mostly known benefits. Physicians can help evaluate these risks and benefits in individual patients and can follow-up and monitor treatments. Careful protection from the sun and avoidance of tanning parlors is advised, and patients who experience a viral infection of the skin should immediately consult their physician.

At the February FDA meeting it was stated that there is currently no certainty of a serious cancer risk associated with the use of these drugs in their topical form. NEASE’s review of the data presented at the meeting found the following:

Unfortunately we simply do not now know the nature and frequency of long-term risks. Many of the problems or concerns discussed at the meeting related to uses of the drugs that differ from those uses approved by the FDA. Such non-approved uses include the use of these drugs on immunosuppressed patients, on patients with an increased risk of cancer, and on children under two years of age; excessive dosing; and, their use without sufficient protection from the sun. Some animal studies utilizing the oral (not topical) formulation of pimecrolimus indicate a potential increased risk of cancer, but some of the animals in these studies had 30 times the highest levels of drug exposure measured in any trial patients on topical therapy. In other animal studies, the topical application of these drugs was sometimes associated with malignancy, but the animals had high exposure due to their absorption.

The use of these drugs on children aged two years and older often improves their eczema and reduces the risks associated with topical steroid therapy. These drugs have improved the quality of life of millions of patients with eczema and their families.

The National Eczema Association for Science and Education (NEASE) represents and advocates for patients with atopic dermatitis (eczema) to improve their health and quality of life. An estimated 10 to 17 million people have this disease, including millions of children. Children with eczema suffer through sleepless nights, itchy and burning skin, incessant scratching, skin infections, and general misery. And parents and family members suffer along with them. Many people are disabled with the condition.

At the February 15^th hearing, Jim Hendricks, a parent of a child with atopic dermatitis/eczema gave the following testimony. Mr. Hendricks tried to explain to the committee the difficulty of living with this disease especially for the child as well as their parents and siblings. (Statement)