Regranex and topicals
In June 2008, the FDA placed a boxed warning on Regranex Gel because of a possible increased rate of mortality observed in patients with cancer. Pediatric Dermatologists caring for children with hemangiomas we have used and continue to use Regranex as a second-line treatment for ulcerated hemangiomas. For this reason we feel that it may be helpful to review the information posted by Johnson and Johnson and the FDA and put this information into perspective for our patients. Of note, none of us has a financial relationship with Johnson and Johnson, the manufacturer of Regranex® nor other conflict of interest to disclose.
BASIS OF THE FDA BOXED WARNING:
A boxed warning has been put on this medication by the FDA which states the following:
“An increased rate of mortality secondary to malignancy was observed in patients treated with three or more tubes of REGRANEX Gel in a postmarketing retrospective cohort study. REGRANEX Gel should only be used when the benefits can be expected to outweigh the risks. REGRANEX Gel should be used with caution in patients with known malignancy”
This warning is based on a two studies for which information became available after the drug was initially approved by the FDA. The largest study compared 2102 patients who used Regranex and 325,313 patients who did not get the medication. They found NO risk of developing cancer with the medication, but did find a higher risk of death from cancer among subjects receiving 3 or more prescriptions for Regranex.
Another study looked at 382 patients with diabetic ulcers treated with Regranex compared to 269 who got a placebo (dummy) medication. They found new or recurrent neoplasms (tumors) in 1% of placebo subjects and 2.7% of Regranex patients for a relative risk of 2.8 but this was not statistically significant. No single type of cancer was identified.
OUR INTERPRETATION OF EVIDENCE PRESENTED
All medications have potential risks and medications can have unexpected side effects, particulary newer ones (Regranex® has been marketed for approximately 10 years ). It is very unusual for topical medications (those put directly on the skin) used in small amounts on small areas of skin for brief periods of times to be absorbed enough to cause serious side effects, such as cancer. The larger study which included more than 2000 patients treated with Regranex® showed no increase in cancer risk, which is very reassuring. The other study, which was smaller, had an equivocal increase in cancer incidence. While the FDA has warned that Regranex® should be used with caution in patients with known cancer, hemangioma is not a form of cancer and there is no evidence that cancers of childhood occur more frequently in children with hemangiomas than in other children. For these reasons, we believe strongly that parents should not be panicked nor expect their child will develop cancer because they used or will use Regranex® for treating an ulcerated hemangioma.
Several important differences are present between infants with hemangiomas and the patients studied:
The patients studied were all adults and all had diabetes, which is not true of any infants with hemangiomas. Skin ulcers in diabetes are typically seen in advanced diabetes and we do not have information about other factors that may have influenced cancer risk, such cigarette smoking, which can make diabetes ulcers worse and also predispose to several forms of cancer.
The group of diabetics in the larger study compared patients using 3 or more prescriptions of Regranex® and those using less or no Regranex®. As mentioned, they did not find an increase in cancer, only an increased risk of cancer deaths. The package insert has always warned against using the medication in people with a known malignancy so this is not a change. Rates of cancer would be expected to be greatly higher in those patients with severe diabetes who are much sicker and, more importantly, much older than infants with hemangiomas. Usually if a certain drug or environmental agent is a carcinogen (cancer-causing) it caused only 1 or 2 types of cancer. Instead, this increase was for deaths from all types of cancer combined.
USE OF REGRANEX® FOR HEMANGIOMAS:
Ulceration is the most common complication seen in infantile hemangiomas. Patients with ulceration experience severe pain, risk of infection, and the potential for significant scarring and anatomic disfigurement. Treatments for ulceration include wound care, antibiotic treatment, laser therapy and systemic medications (which have their own associated risks). In recent years, it has become evident that Regranex® gel applied sparingly, once daily, to persistently-ulcerated hemangiomas often accelerates healing of these open areas.
We have never had a patient (nor have we heard of any from other doctors) in whom Regranex® was used for an ulcerated hemangioma develop cancer. This doesn’t mean it couldn’t happen, but in several years of use and in many hundreds of patients treated we know of no case in which this has happened. Very small amounts of Regranex® are used – these ulcerated areas are usually quite small, and most patients have not needed refills on their medication since many ulcers heal within a few days to weeks after use of the medication (at which time the medication is then stopped).
As in the past, Regranex® is not a first-line treatment for ulcerated hemangiomas – wound care is the mainstay of therapy. As responsible physicians, we will continue to carefully consider whether and when to use Regranex®, until more information becomes available. In our experience, Regranex® can be one of the most effective treatments for refractory ulcerated hemangiomas, but until more is known, we will likely reserve its use for those hemangiomas which have failed to respond to multiple other treatment modalities.
Ilona J. Frieden M.D.
Anthony J. Mancini M.D.
Sarah L. Chamlin M.D.
Denise W. Metry M.D.
NOVA PROVIDES THIS INFORMATION TO FAMILIES AS A RESOURCE. IT IS NOT INTENDED TO ENGAGE IN THE PRACTICE OF MEDICINE OR TO REPLACE THE PHYSICIAN. NOVA DOES NOT CLAIM TO HAVE MEDICAL KNOWLEDGE. NOVA DOES NOT ENDORSE ANY PARTICULAR PHYSICIAN, TREATING FACILITY OR TREATMENT PROTOCAL. IN ALL CASES NOVA AND ITS BOARD OF DIRECTORS RECOMMENDS THAT YOU SEEK THE OPINION OF A PHYSICIAN EXPERIENCED IN THE MANAGEMENT OF HEMANGIOMAS AND VASCULAR MALFORMATIONS.