TCIs and the Black Box: Is the Warning Necessary?

T wo much-needed and often-prescribed medications for treating atopic dermatitis may now be required to carry the heavy weight of a “black box” warning. Pimecrolimus (Elidel) and tacrolimus (Protopic), both topical calcineurin inhibitors (TCIs), were the topic of conversation at a recent meeting of the U.S. FDA’s Pediatrics Advisory Committee. At issue was whether these TCIs are linked to cancers in children. A Look at the Cancer Cases So far, since 2000 when the FDA approved tacrolimus, 21 cases of tumors (three in children) have been reported in patients using tacrolimus, according to an article posted by Reuters. (About 3.5 million prescriptions have been written for this drug since its approval; of these, 7% have been for patients under age 2.) Nine cases of tumors (three in children) have been reported with pimecrolimus since the drug’s approval in 2001. (Pimecrolimus prescriptions are up to 8.7 million since the drug’s approval; 14% have been for patients under age 2.) However, there is no clear data to link any of these cases of cancer to the use of TCIs. So, is the black box warning justified? “The politics of drug safety is pretty loud right now,” commented Skin & Aging’s Chief Medical Editor Dr. Steven Feldman. “For drugs intended for children, there seems to be a desire to do something about safety even if there isn't evidence of a problem. Who can blame them? But as far as I can tell there is no evidence of any real risk in use of Protopic or Elidel — certainly, no evidence that they are riskier than topical corticosteroid alternatives.” Well-known expert Dr. Mark Lebwohl concurred about the lack of evidence. “Overwhelming data exist to show that these drugs are safe and that they are not expected to be harmful when applied topically,” said Dr. Lebwohl, who cited the fact that kidney transplant patients who take large doses of oral tacrolimus on a daily basis for long time periods (and are exposed to larger amounts) regularly experience hypertension and elevated serum creatinine. However, neither of these adverse events occur with topical therapy. “I think the decision to include a black box warning will end up harming patients,” added Dr. Lebwohl, “because it will scare off patients, and they’ll end up using the alternative — a topical steroid in a place where one shouldn’t be used, such as on the face.” What’s the Next Step? The decision to add the black box warning is now in the FDA’s hands. If history is an indicator, the agency is likely to enforce the decision since the FDA usually follows the recommendations made by its advisory panels. Larisa Hubbs Executive Editor lhubbs@hmpcommunications.com

T wo much-needed and often-prescribed medications for treating atopic dermatitis may now be required to carry the heavy weight of a “black box” warning. Pimecrolimus (Elidel) and tacrolimus (Protopic), both topical calcineurin inhibitors (TCIs), were the topic of conversation at a recent meeting of the U.S. FDA’s Pediatrics Advisory Committee. At issue was whether these TCIs are linked to cancers in children. A Look at the Cancer Cases So far, since 2000 when the FDA approved tacrolimus, 21 cases of tumors (three in children) have been reported in patients using tacrolimus, according to an article posted by Reuters. (About 3.5 million prescriptions have been written for this drug since its approval; of these, 7% have been for patients under age 2.) Nine cases of tumors (three in children) have been reported with pimecrolimus since the drug’s approval in 2001. (Pimecrolimus prescriptions are up to 8.7 million since the drug’s approval; 14% have been for patients under age 2.) However, there is no clear data to link any of these cases of cancer to the use of TCIs. So, is the black box warning justified? “The politics of drug safety is pretty loud right now,” commented Skin & Aging’s Chief Medical Editor Dr. Steven Feldman. “For drugs intended for children, there seems to be a desire to do something about safety even if there isn't evidence of a problem. Who can blame them? But as far as I can tell there is no evidence of any real risk in use of Protopic or Elidel — certainly, no evidence that they are riskier than topical corticosteroid alternatives.” Well-known expert Dr. Mark Lebwohl concurred about the lack of evidence. “Overwhelming data exist to show that these drugs are safe and that they are not expected to be harmful when applied topically,” said Dr. Lebwohl, who cited the fact that kidney transplant patients who take large doses of oral tacrolimus on a daily basis for long time periods (and are exposed to larger amounts) regularly experience hypertension and elevated serum creatinine. However, neither of these adverse events occur with topical therapy. “I think the decision to include a black box warning will end up harming patients,” added Dr. Lebwohl, “because it will scare off patients, and they’ll end up using the alternative — a topical steroid in a place where one shouldn’t be used, such as on the face.” What’s the Next Step? The decision to add the black box warning is now in the FDA’s hands. If history is an indicator, the agency is likely to enforce the decision since the FDA usually follows the recommendations made by its advisory panels. Larisa Hubbs Executive Editor lhubbs@hmpcommunications.com