Why is a treatment used safely for decades disappearing from U.S. pharmacies?
By Jan Bowers, contributing writer, July 01, 2011
Cantharidin, a compound used successfully for more than 50 years in treating molluscum contagiosum, is becoming increasingly difficult for dermatologists to obtain. In the apparent absence of any new safety evidence regarding the topical use of cantharidin in the physician’s office, at least one regional office of the U.S. Food and Drug Administration (FDA) has blocked shipment of raw cantharidin crystals from Canada (originally exported from China). A compounding pharmacy in Missouri received a warning letter from the FDA stating that cantharidin is not an active ingredient contained in any FDA-approved drug and that the FDA does not sanction its use in pharmacy compounding. As a result of the FDA’s increased scrutiny, commercial suppliers in the U. S. can no longer purchase raw cantharidin crystals, according to a major dermatology drug manufacturer. In addition, some hospital pharmacies with existing supplies have stopped dispensing the compound to dermatologists, who are left wondering why a safe and effective treatment option has been taken from their patients.
“For some reason, in the past two years or so, the FDA starting rattling its saber a bit and sent a threatening letter to at least one compounding pharmacy, with the result that we practitioners in medical centers are unable to use this medicine,” said Robert Sidbury, MD, associate professor in the department of pediatrics and chief of the division of dermatology at Seattle Children’s Hospital and the University of Washington School of Medicine. “Possibly it’s just a misunderstanding of the dangers, but it would be nice for us to know what the FDA has come across in the last couple of years that has caused them to start sending out these letters.” Beetle juice works
Cantharidin is extracted from the blister beetle, a member of the family Meloidae. In historical records dating back to Hippocrates, it appears as a remedy for a variety of disorders including dropsy and rabies. Dermatologists have used cantharidin to treat molluscum and warts at least since the mid-20th century. While the incidence of molluscum is highest in children under five years old, adults also contract this common virus, frequently through sexual contact.[pagebreak]
According to a retrospective study of cantharidin therapy co-authored by Dr. Sidbury, Nanette B. Silverberg, MD, and Anthony J. Mancini, MD, and published in the Journal of the American Academy of Dermatology
(2000;43:503-507), cantharidin is a protein phosphatase inhibitor that penetrates the epidermis and induces vesiculation through acantholysis. Combined with flexible collodion, it forms a viscous fluid that the physician applies sparingly to each lesion, with instructions to the parent (or adult patient) to rinse the treated areas with water after four to six hours. In the JAAD
study, of 300 children followed after treatment of molluscum lesions with cantharidin, 90 percent experienced clearing and an additional 8 percent improved.
“This treatment is extremely effective, safe, and well-tolerated,” said Dr. Mancini, who is professor of pediatrics and dermatology at Northwestern University Feinberg School of Medicine and head of the division of pediatric dermatology at Children’s Memorial Hospital. “We used it in thousands of patients until two years ago. Taking that treatment away is a huge disservice to our patients.” Although molluscum lesions generally clear on their own from six months to two years after they appear, they can become inflamed, infected, and cause considerable discomfort, Dr. Mancini said. “In addition, they’re somewhat unsightly and clearly pose a significant issue for other parents who may not want their kids near a child who has a contagious condition.”
Alternatives to cantharidin include cryotherapy, curettage, imiquimod, and tretinoin, all of which have significant drawbacks. “We’re not typically going to freeze or scrape off benign lesions on a very young child because these are painful, emotionally traumatizing treatments,” Dr. Mancini said. “Topical creams that have been used off-label are very irritating to these kids. Cantharidin was not only efficacious and well-tolerated, but it was accepted by parents and children alike. Children would come back for their ‘beetle juice’ because there was no pain associated with the in-office application.” Now that cantharidin is no longer available to his group, Dr. Mancini said, parents seeking treatment for their child’s molluscum are told to “watch and wait, or see if your pediatrician or community dermatologist offers this treatment, because we unfortunately cannot.”[pagebreak] Importation issues
Cantharidin has been on the FDA’s radar since the early 1990s, according to Deborah Grafelman, president of Delasco Dermatologic Lab and Supply, Inc., in Council Bluffs, Iowa. “There were at least five cantharidin products on the market for a very long time, until in 1993 the FDA said, ‘We don’t allow grandfathered drugs, and this drug never went through the New Drug Application (NDA) process,’” she said. “But it was such a small market for the three manufacturers that none could afford to conduct the clinical trials, so they pulled the products from the shelf.”
Upon the advice of a regulatory affairs consultant, Delasco began selling kits containing the raw materials of the compound, with instructions for the physician or hospital pharmacy to mix the cantharidin crystals with the collodion vehicle. “We did this for years, and then other companies that are compounding pharmacies (and thus allowed to mix the drug) purchased the raw materials and began selling the compound,” Grafelman said. “But in 1998 our California supplier said the FDA was stopping their importation of cantharidin from China, and we went without it for a long time. In 2009 we found a Canadian supplier and imported one shipment from them. The next time we tried to import it, the FDA blocked it and said it’s an unapproved drug.” Grafelman contends that because the cantharidin crystals constitute a raw material, not a drug, there is no FDA regulation prohibiting their sale. “If we could get the raw material we would still be dispensing it,” she said. “It was on the market, safely used for 40 years. It really doesn’t make any sense. There are a few compounding pharmacies around the country that still have some, but as soon as they run out, that’s going to be it.”
A path to the legal use of cantharidin seemed to be opening in 1999, when the FDA published in the Federal Register (Vol. 64, No. 4) a proposed list of bulk drug substances that could be used in pharmacy compounding, pursuant to the Food and Drug Administration Modernization Act of 1997. In nominating cantharidin as one of 20 substances proposed for inclusion on the list, the FDA said, “Although cantharidin is an extremely toxic substance, it is apparently used only in the professional office setting and not dispensed for home use.” The list was never finalized, however, so the legal status of cantharidin remained unchanged.[pagebreak] Dermatologists react
Hearing multiple reports about problems obtaining cantharidin, Dr. Sidbury began seeking clarification from the FDA prior to presenting at the Society of Pediatric Dermatology annual meeting last summer. “I tried for a month to get hold of someone at the FDA, and finally received a rather opaque response suggesting that I could use cantharidin on my patients only if I submitted an Investigational New Drug (IND) application,” he said. “That’s not even appropriate, because it’s normally done in the context of a clinical study.” Dr. Sidbury said the controversy has caused his hospital pharmacy to cease providing the compound. “There are some community providers here who offer it; I’m not sure if they’re getting rid of old stocks or if they still have free access, as they have in the past. But we cannot use it, and it’s a big problem.”
One dermatologist exploring the feasibility of a multi-site clinical trial said she was also temporarily unable to use cantharidin. “The pharmacist at my hospital recently informed me that state pharmacy board regulations dictated that I could no longer use cantharidin,” said Elaine Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University School of Medicine and Cardinal Glennon Children’s Hospital. “In order to appeal this decision, I provided numerous publications from peer-reviewed medical journals supporting the use of cantharidin as standard of care for treatment of molluscum in children. I also called suppliers; Delasco told me they couldn’t get cantharidin anymore, but a compounding pharmacy in St. Louis is still selling it, even though they received a warning letter from the FDA, which they interpreted as allowing continued sale to clinicians.”
After a lengthy appeal, Dr. Siegfried’s hospital pharmacy committee approved her use of cantharidin, compounded in-house from a stock supply that the hospital has on the shelf. “Our pharmacy director contacted the Kansas City FDA office. After providing an explanation of our request, he was told that as long as it is applied In our clinic, the FDA would not get involved,” Dr. Siegfried said.[pagebreak]
“I am thrilled that I can continue to use cantharidin, because molluscum can be a very difficult condition to treat in children with eczema. Online chat rooms are a testimonial to the angst of these children and their parents, as well as the advantage taken by website merchants selling over-the-counter snake oil remedies.Some families spend a fortune on these unproven treatments.The situation is heart-breaking.” Academy investigates
Reports of members’ difficulties in obtaining cantharidin prompted the American Academy of Dermatology Association to launch efforts to pinpoint the shortages and work with the FDA to understand and address their concerns. “I haven’t a clue as to why the FDA started sending letters to pharmacies about cantharidin,” said Mary E. Maloney, MD, chief of the division of dermatology at the University of Massachusetts Medical School and chair of the Academy’s Regulatory Policy Committee. “Cantharidin is not on the approved compounding list, and why it is not is not clear to any of us on the outside. We have a huge amount of data that show how effective and safe it is; however, those aren’t always controlled studies.”
The Academy is trying to resolve the issue with the FDA without a new drug application from a drug company. “That would be too expensive and probably not a reality,” Dr. Maloney said. “We’re going to try to get them to accept the multiple reports we have, and talk to the commissioner to see if we can change the course in that way. This is a really important issue — for all of us, not just pediatric dermatologists — and we’re just going to have to work diligently to change the outcome.”
The Academy is learning that cantharidin shortages are regional, said Barbara Greenan, the Academy’s senior director of government affairs. “We haven’t been able to determine that the FDA has done anything at the federal level to block cantharidin importation, but they seem to be blocking it in some regions,” she explained. “Some dermatologists can still get cantharidin from their local compounding pharmacies with no problems, and others have been completely unable to get it for some time now. We don’t have a good sense yet of how that regional pattern looks, but we’ll know better as we get more feedback from members,” she added.
Although some dermatologists in private practice are buying cantharidin from Canadian manufacturers, the Academy does not encourage this, Greenan said. “It’s risky, because it’s not subject to the same review and regulatory scheme as drugs that are appropriately Imported into the U.S.,” she pointed out. “When we’re asked by members, we strongly suggest that they stick with the trusted sources in the U.S., and we’ll work with the FDA to restore that. But we understand what it’s like in practice, and know they have to use their best professional judgment.”
After hearing of the issue last year, the Academy reached out to members in the spring for more information and has heard from more than 50 dermatologists, Greenan said. “We’re continuing to solicit information about our members’ experience with cantharidin access: if they’re having trouble getting it, when that trouble started, who is their compounding pharmacist. This will give us a better picture of the geography and the circumstances, so that we can communicate that to the FDA. These things are never a quick fix, but we understand the magnitude of the problem and are working as closely with the FDA as possible to find a solution.”
Having trouble finding cantharidin?
Members are encouraged to submit a detailed account of any difficulties they encounter regarding access to cantharidin to Amanda Grimm, regulatory policy specialist, at firstname.lastname@example.org.