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 20th, the U.S. Food and Drug Administration approved a black warning and a medication guide.

In the wake of the 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 copy of the full 21-page report can be obtained free of charge by patients or physicians by contacting the NEASE office.