Drug Update
Public Health Advisory Issued for Elidel and Prolopic
According to FDA MedWatch and the U.S. Food and Drug Administration (FDA) Web site (www.fda.org), on March 10, 2005 the FDA issued a public health advisory to inform health care providers and patients about a potential cancer risk from use of Elidel ” (pimecrolimus) and Protopic” (tacrolimus), products that are applied to the skin for treatment of atopic dermatitis (ezcema). Elidel cream and Protopic ointment are topical immunosuppressant calcineurin inhibitors and are the only approved drug products in this class.
This concern is based on information from animal studies, case reports in a small number of patients, and how these drugs work. Animal studies have shown that three different species of animals developed cancer following exposure to these drugs applied topically or given by mouth, including mice, rats, and a recent 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. It may take human studies of 10 years or longer to determine if use of Elidel or Protopic is linked to cancer, but in the meantime this risk is uncertain and the FDA advises that Elidel and Protopic be used only as labeled for patients who have failed treatment with other therapies. The FDA recommends health care providers, patients, and caregivers consider the following guidelines:
* Use Elidel and Protopic only as second-line agents for short- term and intermittent treatment of atopic dermatitis (eczema) in patients unresponsive to, or intolerant of other treatments.
* Avoid use of Elidel and Protopic in children younger than 2 years of age.
* Use Elidel and Protopic only for short periods of time, not continuously.
* Children and adults with a weakened or compromised immune system should not use Elidel or Protopic.
* Use the minimum amount of Elidel or Protopic needed to control the patient’s symptoms.
Protopic was approved in December 2000 and Elidel in December 2001. Since their approval, the FDA has received reports of lymphoma and skin cancer in children and adults treated with Elidel or Protopic; whether the reported cancers are associated with these products has not been clearly established. Based on the advice of the FDA Pediatric Advisory Committee, which met in February 2005 to review these findings, the FDA will require labeling changes for Elidel and Protopic, including the placement of a boxed warning about the potential cancer risk. In addition, the FDA will work with the commercial sponsors of the drugs to develop and implement a Medication Guide (MedGuide) to provide this information and instructions about appropriate use of Elidel and Protopic to patients, their families, and caregivers.
On April 8, 2005 the DNA Board of Directors sent a letter to the FDA voicing its concern about the potential black box warning for Elidel and Protopic. The Board stated that “as advocates for our patients, we hope you will consider the serious consequences of restricting the calcineurin inhibitors to the extent that patients cannot receive the treatments they require to control their disease.” The DNA cited the effectiveness of the drugs when used appropriately.
Novartis Pharmaceuticals Corp., makers of Elidel, issued a response to the advisory on March 10, 2005: “Patient safety is of paramount concern to Novartis. We agree with the Food and Drug Administration that Elidel (pimecrolimus) Cream 1% should be used as directed and as indicated. We are working closely with the FDA to revise Elidel prescribing information to ensure that physicians and patients have the information they need to effectively treat eczema. FDA has informed Novartis that we will begin discussion about type of label and the exact wording contained in the label within the next few weeks. There is no change in the label at this time. Novartis agrees that patients suffering from mild-to-moderate eczema need to be informed about the safe and effective use of Elidel, but we believe a recommendation to add a black box warning to the label is unsubstantiated by clinical evidence and experience in more than five million patients worldwide. In addition, we are concerned about any confusion there may be in the public at this time. In clinical studies started over eight years ago and involving more than 19,000 patients worldwide, including more than 2,600 infants and 7,300 children, Elidel was found to be effective with a favorable safety profile. No causal relationship was established between the use of Elidel Cream and development of malignancy. To profide further evidence of the safety of Elidel, Novartis has initiated two long- term clinical studies and an observational registry with thousands of pediatric patients.”
FDA Mandates Registry for Patients Taking Isotretinoin
The U.S. Food and Drug Administration (FDA) announced plans to start a centralized registry to monitor all patients who take isotretinoin, an acne medication that can cause serious birth defects. The registry, which starts in July 2005, will track patients taking the drug, practitioners who prescribe it, and pharmacies that dispense it. Two articles in the January 2005 issue of Dermatology Times explain the goals of the registry and debate both the benefits and the negatives of the issue.
Christine S. Parker, public affairs specialist for the FDA, explains that there are multiple goals to mandating the registry, but one primary concern is ensuring that females of childbearing age are not pregnant at the beginning of treatment, and do not become pregnant during treatment. She says, “To accomplish these goals, the strengthened program will seek to ensure that all patients are fully informed about the potential risks and benefits of isotretinoin use and the steps they can take to minimize these risks, and that they receive appropriate counseling and education throughout their treatment course.”
Details of regulations have not yet been finalized, but it is known that there will be a large confidential database, or registry, for clinicians, patients, and pharmacies. The joint database will be shared by the four manufacturers of isotretinoin, which are Roche Pharmaceuticals, Barr Laboratories, Inc., Mylan Laboratories, Inc., and Ranbaxy Laboratories, Ltd. The companies are responsible for maintaining the registry, monitoring efficacy, and ensuring compliance. According to the FDA, privacy concerns of registrants are of critical importance, and will continue to be taken into account as program details are finalized.
To date, the companies have only monitored prescribers as part of a voluntary program. Under the new registry, however, before a pharmacy can fill a patient’s first isotretinoin prescription, proper guidelines must be followed. The registry must contain documentation that the patient received education about the drug from the prescriber, that an appropriately timed pregnancy test was negative, and that patients completed informed consent as well as education and risk management components. For repeat prescriptions, there must be evidence of ongoing patient education, another timely negative pregnancy test, and repeated patient completion of education and risk management components.
Hilary E. Baldwin, MD, an associate professor of clinical dermatology at the State University of New York Downstate, Brooklyn, explains the complications of this program. She says under this scenario, “a patient would come to see me a couple days prior to their menstrual cycle. I would order a urine or blood pregnancy test. The patient would go get it done. The lab would sign off on the fact that it had been done. A couple days later, I would sign off to indicate that I had looked at it and it was negative, thereby allowing the pharmacy to release the drug to the patient when she showed up with a prescription. The bottom line is that this is going to be very complicated. It’s going to take an awful lot of paperwork. For those of us who prescribe a lot of isotretinoin, it’s going to be a considerable headache…” As for concerns that doctors may stop prescribing isotretinoin due to tighter regulations and more paperwork, Dr. Baldwin concludes that dermatologists take an oath to do the best for their patients, and if a patient requires isotretinoin, the dermatologist needs to prescribe it to her/him, or refer the patient to someone who will.
Another concern is that patients will not want to fill out lengthy consent forms, or follow the regulations set by the FDA, which may drive them to the Internet for sales because it is easier and cheaper. The problem lies in the fake pharmacies that sell drugs without a prescription, and no one will ensure female patients do not become pregnant. Also, according to Dr. Baldwin, there are more than 30 true generic brands of isotretinoin available around the world, and it is unclear what a patient may receive, or if it is really isotretinoin.
A supporter of the new regulations is Neil Sadick, MD, FACP, FAACS, a New York City dermatology private practitioner, and clinical professor in the department of dermatology, Weill Medical College of Cornell University. He agrees that the PDA’s rules are warranted. He says, “The only real problems that have occurred with (isotretinoin) have been basically based on pregnancy issues…I think it does need to be regulated. Otherwise it will end up like thalidomide, and we’ll see a lot of deformed \children and a lot of unnecessary fetal death.” Another supporter is Barbara R. Reed, MD, chair of the Ad Hoc Task Force on Isotretinoin for the American Academy of Dermatology Association. She believes clinicians, pharmacies, and patients will initially have a learning curve, but once the program is under way, it will not cause great inconvenience.
Copyright Anthony J. Jannetti, Inc. Jun 2005