FDA Warnings

FDA Warning On January 19, 2006 the Food & Drug Administration (FDA) approved new labeling requirements for two topical eczema drugs, Elidel Cream (pimecrolimus) and Protopic Ointment (tacrolimus). The labeling will be updated with a black box warning about a possible risk of cancer. The FDA action in January 2006 follows an agency advisory committee recommendation in February 2005 that Elidel cream and Protopic ointment carry the label warning notice.

In 2003 an FDA advisory committee recommended that Astellas (formerly known as Fujisawa) and Novartis revise their product inserts to inform patients of the significant adverse events such as cancer risks from these products. A serious adverse risk is defined by the FDA as: any experience that resulted in death, was life threatening, required in-patient hospitalization, or prolongation of existing hospitalization, resulting in persistent or significant disability/incapacity or congenital anomaly/birth defect or considered an important medical event.

Accumulating scientific evidence of deaths and serious repercussions, particularly in young children, led the FDA to its March 2005 agreement with the Advisory Committee that a "Black Box" warning of cancer risks was needed for these two topical ointments. The "Black Box" is the severest of warnings the FDA can mandate. A January 2005 FDA study found: The immunosuppressive effects of these topical products in animals, manifested primarily as lymphoma formation, are strong, consistent and compelling. The biological relevance of these animals findings to humans exposed to these drugs cannot be excluded. In addition, immunosuppression is the proposed mechanism of action of Protopic and Elidel.

This cancer risk warning was endorsed by the FDA because, “[b]ased on the totality of scientific information available thus far which includes animal carcinogenicity signal both in mice and monkeys, post-marketing tumor-related adverse event reports coupled with the increased absorption in atopic dermatitis resulting in greater systemic exposure.”

The evidence raises serious safety concerns in children regarding the potential for carcinogenicity in humans treated with these agents. These products are being widely used to treat atopic dermatitis, a non-life threatening disease, and heavily advertised for use in young children without appreciation by parents and physicians regarding the potential for carcinogenic risk.

Protopic Elidel

FDA Restrictive Approval

Protopic was approved by the FDA in 2000. Elidel received its NDA in 2001. There were, however, some stringent restrictions placed by the FDA on both products which are significant in understanding. These limitations were undermined by the aggressive marketing practices of Novartis and Astellas (formerly known as Fujisawa). Initially, these products were to be only second line therapies. This meant Protopic and Elidel should not be prescribed by physicians in the first instance. The more traditional and proven topical corticosteroids were to be the first line of therapy. Only if steroids did not work or could not be used, then prescribing Protopic or Elidel was appropriate. Despite this restriction both drug companies have been intentionally marketing these prescribed products to dermatologists and pediatricians for use in the onset of treatment, contrary. FDA investigators concur in this fact: The increasing use may be related to aggressive and inappropriate advertising with portrayal of these products as safer than steroids and the implication they can be used as first-line therapy and for unlimited periods of time.

Second, these two immunosuppressants were approved only for children between ages 2 - 16 years. This was due in part to the sensitivity of children to reactions and concerns about drug absorption into the blood system. For Protopic dosage levels for these age kids had to be .03% of the active ingredient – tacrolimus – instead of the stronger 0.1% strength authorized for adults. This is again very important to understand. Studies on the drug had found the higher dosage resulted in absorption into the blood of the active suppressive agent, and the more serious adverse events. The NDA medical file on Protopic stated: Because pediatric patients may absorb more of the Tacrolimus into their blood, and because of the unexpected long term exposure to the Tacrolimus ointment during their life, it seems that there is no sufficient justification for the use of the 0.1% ointment in pediatric patients.

Yet, due to intentional marketing and promotions by Novartis and Astellas (formerly known as Fujisawa), as the prescription data clearly establishes, both drugs have been prescribed indiscriminately from both dosage level and age groups. The manufacturers’ marketing efforts are fueling these results, and physicians do not appreciate the risks.

Third, and most important, neither drug – Protopic nor Elidel – were approved for children under 2 years of age or below. The reason was that tests demonstrated both an unknown effect upon the immune system on such young children and the long term exposure consequences from the drugs. Yet, prescription data in 2004 showed approximately 13% of Elidel and 8% of Protopic were being prescribed for children 2 or under. Novartis and Astellas (formerly known as Fujisawa) know this. It is off label use. Once again, their marketing promotions, presentations made to physicians by the sales force, and outside paid endorsers saying no safety problem because these are “steroid free” products are believed to be contributing to this, all of which is traceable directly back to the manufacturers.

The second and third points above are referred to as off-label use. Novartis and Astellas (formerly known as Fujisawa) will have little or no defense to this type of intentional off-label promotion. Further, they are doing so with full knowledge of the repercussions of their actions.

FDA Warnings

FDA Restrictive Approval

FDA Warns

Pose Cancer Risk

The Law Offices of Larry M. Roth, P.A.