T he main reasons cited by the FDA for issuing a public health advisory on topical calcineurin inhibitors (TCIs), which the agency did on March 10, include that there is a potential risk of cancer. According to what the agency wrote in the advisory, this concern is “based on information from animal studies, case reports in a small number of patients, and how these drugs work.” To date, more than 12 million prescriptions of pimecrolimus (Elidel) and tacrolimus (Protopic) have been written; 14% and 7%, respectively, have been for children under age 2, according to the FDA. Thirty cases of tumors, 6 of which were in children, have been reported in patients using these drugs, the FDA documented. However, these tumors were not clearly linked to use of topical calcineurin inhibitors (TCIs). So the actions taken by the FDA have left some dermatologists puzzled. Disagreeing With the Decision According to Mark Lebwohl, M.D., Professor and Chairman, Department of Dermatology at the Mount Sinai School of Medicine, “Even when we look at research with malignancy-prone animals that were given maximum human exposures to the cream or ointment, we’re not seeing evidence of a problem,” he noted. “In studies of mice and rats that were given these drugs either orally at less than 258 times maximum human exposure or topically in an alcohol base, which enhanced penetration at doses less than 26 times the maximum human level, we didn’t see a signal that these animals may develop lymphomas,” he said. In fact, research with these drugs has not raised any red flags. “There is overwhelming data showing that these drugs are safe and that they are not expected to be harmful in large amounts,” noted Dr. Lebwohl. “We know that tacrolimus has been given orally for kidney transplant patients in high-dose form on a daily basis over the long term. The main types of adverse reactions we’ve seen with these patients are elevated blood pressure and elevated serum creatinine levels. Transplant patients in general (who are always on long-term anti-transplant rejection medicines) statistically have a 10-fold increase in lymphoma,” said Dr. Lebwohl. “However, what we’ve seen with tacrolimus and pimecrolimus is that these topical drugs are absorbed in such limited amounts, we never see blood pressure elevation or increased serum creatinine levels — which should be the first signs that a patient is having an adverse reaction.” Dermatologist James Q. Del Rosso, D.O., who is Clinical Assistant Professor in the Department of Dermatology at the University of Nevada School of Medicine in Las Vegas, also was perplexed about the FDA’s addition of the black box warning to Elidel and Protopic. “To place a black box warning without sufficient scientific proof serves to only increase anxiety among practitioners and patients,” he commented. “It is reasonable to suggest that pharmacosurveillance be enhanced and that reasonable warnings be placed. However, the black box warning implies that the FDA has proof. In this case, it seems to be a knee-jerk reflex as opposed to a well-thought-out scientific discovery.” Dr. Lebwohl added, “The interaction between the FDA and the pharmaceutical companies shouldn’t become hostile; what’s missing is caring for the patient.” According to the FDA’s public health advisory, the agency justified its actions by stating, “it may take human studies of 10 years or longer to determine if use of Elidel or Protopic is linked to cancer. In the meantime, this risk is uncertain and FDA advises that Elidel and Protopic should be used only as labeled, for patients who have failed treatment with other therapies.” Where to Go from Here? According to Lawrence F. Eichenfield, M.D., Clinical Professor of Pediatrics and Medicine (Dermatology) and Chief of Pediatric Dermatology at the University of California, San Diego and the Children’s Hospital, San Diego, the recent action by the FDA regarding TCIs is intended to reposition the use of these agents to be consistent with the spirit of their original approval (at least until the risk of carcinogenesis can be better characterized). “When this family of agents was originally approved by the FDA,” explained Dr. Eichenfield, “these characteristics were well understood and consequently the therapy was intended as a second-line treatment. However,” he added, “the known potential association of cancer risk with these immunomodulating agents had not been widely publicized.” The FDA made a list of recommendations for healthcare providers to consider when prescribing Elidel or Protopic. The agency’s suggestions include the following: • Second-line therapies. Use TCIs only as second-line agents and for short-term and intermittent treatment for patients who have not responded, or are intolerant of, other treatments. • Prescriptions for young children. Avoid using Elidel or Protopic in children younger than age 2 because the effects of these agents on the developing immune system are not known. • Compromised immune systems. Children or adults with weakened immune systems should not use these drugs. • Mimimum amounts. Use the minimum amount of Elidel or Protopic necessary to control a patient’s symptoms. Dr. Eichenfield explained that the recent news from the FDA has not greatly altered his approach to patient management, in that topical steroids are generally advised as first-line therapy. However, he maintained that TCIs are still valuable therapeutic agents. For more information on Dr. Eichenfield’s algorithm for treating atopic dermatitis patients, see the chart below.
What’s the Next step for TCIs?
T he main reasons cited by the FDA for issuing a public health advisory on topical calcineurin inhibitors (TCIs), which the agency did on March 10, include that there is a potential risk of cancer. According to what the agency wrote in the advisory, this concern is “based on information from animal studies, case reports in a small number of patients, and how these drugs work.” To date, more than 12 million prescriptions of pimecrolimus (Elidel) and tacrolimus (Protopic) have been written; 14% and 7%, respectively, have been for children under age 2, according to the FDA. Thirty cases of tumors, 6 of which were in children, have been reported in patients using these drugs, the FDA documented. However, these tumors were not clearly linked to use of topical calcineurin inhibitors (TCIs). So the actions taken by the FDA have left some dermatologists puzzled. Disagreeing With the Decision According to Mark Lebwohl, M.D., Professor and Chairman, Department of Dermatology at the Mount Sinai School of Medicine, “Even when we look at research with malignancy-prone animals that were given maximum human exposures to the cream or ointment, we’re not seeing evidence of a problem,” he noted. “In studies of mice and rats that were given these drugs either orally at less than 258 times maximum human exposure or topically in an alcohol base, which enhanced penetration at doses less than 26 times the maximum human level, we didn’t see a signal that these animals may develop lymphomas,” he said. In fact, research with these drugs has not raised any red flags. “There is overwhelming data showing that these drugs are safe and that they are not expected to be harmful in large amounts,” noted Dr. Lebwohl. “We know that tacrolimus has been given orally for kidney transplant patients in high-dose form on a daily basis over the long term. The main types of adverse reactions we’ve seen with these patients are elevated blood pressure and elevated serum creatinine levels. Transplant patients in general (who are always on long-term anti-transplant rejection medicines) statistically have a 10-fold increase in lymphoma,” said Dr. Lebwohl. “However, what we’ve seen with tacrolimus and pimecrolimus is that these topical drugs are absorbed in such limited amounts, we never see blood pressure elevation or increased serum creatinine levels — which should be the first signs that a patient is having an adverse reaction.” Dermatologist James Q. Del Rosso, D.O., who is Clinical Assistant Professor in the Department of Dermatology at the University of Nevada School of Medicine in Las Vegas, also was perplexed about the FDA’s addition of the black box warning to Elidel and Protopic. “To place a black box warning without sufficient scientific proof serves to only increase anxiety among practitioners and patients,” he commented. “It is reasonable to suggest that pharmacosurveillance be enhanced and that reasonable warnings be placed. However, the black box warning implies that the FDA has proof. In this case, it seems to be a knee-jerk reflex as opposed to a well-thought-out scientific discovery.” Dr. Lebwohl added, “The interaction between the FDA and the pharmaceutical companies shouldn’t become hostile; what’s missing is caring for the patient.” According to the FDA’s public health advisory, the agency justified its actions by stating, “it may take human studies of 10 years or longer to determine if use of Elidel or Protopic is linked to cancer. In the meantime, this risk is uncertain and FDA advises that Elidel and Protopic should be used only as labeled, for patients who have failed treatment with other therapies.” Where to Go from Here? According to Lawrence F. Eichenfield, M.D., Clinical Professor of Pediatrics and Medicine (Dermatology) and Chief of Pediatric Dermatology at the University of California, San Diego and the Children’s Hospital, San Diego, the recent action by the FDA regarding TCIs is intended to reposition the use of these agents to be consistent with the spirit of their original approval (at least until the risk of carcinogenesis can be better characterized). “When this family of agents was originally approved by the FDA,” explained Dr. Eichenfield, “these characteristics were well understood and consequently the therapy was intended as a second-line treatment. However,” he added, “the known potential association of cancer risk with these immunomodulating agents had not been widely publicized.” The FDA made a list of recommendations for healthcare providers to consider when prescribing Elidel or Protopic. The agency’s suggestions include the following: • Second-line therapies. Use TCIs only as second-line agents and for short-term and intermittent treatment for patients who have not responded, or are intolerant of, other treatments. • Prescriptions for young children. Avoid using Elidel or Protopic in children younger than age 2 because the effects of these agents on the developing immune system are not known. • Compromised immune systems. Children or adults with weakened immune systems should not use these drugs. • Mimimum amounts. Use the minimum amount of Elidel or Protopic necessary to control a patient’s symptoms. Dr. Eichenfield explained that the recent news from the FDA has not greatly altered his approach to patient management, in that topical steroids are generally advised as first-line therapy. However, he maintained that TCIs are still valuable therapeutic agents. For more information on Dr. Eichenfield’s algorithm for treating atopic dermatitis patients, see the chart below.
T he main reasons cited by the FDA for issuing a public health advisory on topical calcineurin inhibitors (TCIs), which the agency did on March 10, include that there is a potential risk of cancer. According to what the agency wrote in the advisory, this concern is “based on information from animal studies, case reports in a small number of patients, and how these drugs work.” To date, more than 12 million prescriptions of pimecrolimus (Elidel) and tacrolimus (Protopic) have been written; 14% and 7%, respectively, have been for children under age 2, according to the FDA. Thirty cases of tumors, 6 of which were in children, have been reported in patients using these drugs, the FDA documented. However, these tumors were not clearly linked to use of topical calcineurin inhibitors (TCIs). So the actions taken by the FDA have left some dermatologists puzzled. Disagreeing With the Decision According to Mark Lebwohl, M.D., Professor and Chairman, Department of Dermatology at the Mount Sinai School of Medicine, “Even when we look at research with malignancy-prone animals that were given maximum human exposures to the cream or ointment, we’re not seeing evidence of a problem,” he noted. “In studies of mice and rats that were given these drugs either orally at less than 258 times maximum human exposure or topically in an alcohol base, which enhanced penetration at doses less than 26 times the maximum human level, we didn’t see a signal that these animals may develop lymphomas,” he said. In fact, research with these drugs has not raised any red flags. “There is overwhelming data showing that these drugs are safe and that they are not expected to be harmful in large amounts,” noted Dr. Lebwohl. “We know that tacrolimus has been given orally for kidney transplant patients in high-dose form on a daily basis over the long term. The main types of adverse reactions we’ve seen with these patients are elevated blood pressure and elevated serum creatinine levels. Transplant patients in general (who are always on long-term anti-transplant rejection medicines) statistically have a 10-fold increase in lymphoma,” said Dr. Lebwohl. “However, what we’ve seen with tacrolimus and pimecrolimus is that these topical drugs are absorbed in such limited amounts, we never see blood pressure elevation or increased serum creatinine levels — which should be the first signs that a patient is having an adverse reaction.” Dermatologist James Q. Del Rosso, D.O., who is Clinical Assistant Professor in the Department of Dermatology at the University of Nevada School of Medicine in Las Vegas, also was perplexed about the FDA’s addition of the black box warning to Elidel and Protopic. “To place a black box warning without sufficient scientific proof serves to only increase anxiety among practitioners and patients,” he commented. “It is reasonable to suggest that pharmacosurveillance be enhanced and that reasonable warnings be placed. However, the black box warning implies that the FDA has proof. In this case, it seems to be a knee-jerk reflex as opposed to a well-thought-out scientific discovery.” Dr. Lebwohl added, “The interaction between the FDA and the pharmaceutical companies shouldn’t become hostile; what’s missing is caring for the patient.” According to the FDA’s public health advisory, the agency justified its actions by stating, “it may take human studies of 10 years or longer to determine if use of Elidel or Protopic is linked to cancer. In the meantime, this risk is uncertain and FDA advises that Elidel and Protopic should be used only as labeled, for patients who have failed treatment with other therapies.” Where to Go from Here? According to Lawrence F. Eichenfield, M.D., Clinical Professor of Pediatrics and Medicine (Dermatology) and Chief of Pediatric Dermatology at the University of California, San Diego and the Children’s Hospital, San Diego, the recent action by the FDA regarding TCIs is intended to reposition the use of these agents to be consistent with the spirit of their original approval (at least until the risk of carcinogenesis can be better characterized). “When this family of agents was originally approved by the FDA,” explained Dr. Eichenfield, “these characteristics were well understood and consequently the therapy was intended as a second-line treatment. However,” he added, “the known potential association of cancer risk with these immunomodulating agents had not been widely publicized.” The FDA made a list of recommendations for healthcare providers to consider when prescribing Elidel or Protopic. The agency’s suggestions include the following: • Second-line therapies. Use TCIs only as second-line agents and for short-term and intermittent treatment for patients who have not responded, or are intolerant of, other treatments. • Prescriptions for young children. Avoid using Elidel or Protopic in children younger than age 2 because the effects of these agents on the developing immune system are not known. • Compromised immune systems. Children or adults with weakened immune systems should not use these drugs. • Mimimum amounts. Use the minimum amount of Elidel or Protopic necessary to control a patient’s symptoms. Dr. Eichenfield explained that the recent news from the FDA has not greatly altered his approach to patient management, in that topical steroids are generally advised as first-line therapy. However, he maintained that TCIs are still valuable therapeutic agents. For more information on Dr. Eichenfield’s algorithm for treating atopic dermatitis patients, see the chart below.
