What does a black box warning mean

Black box warning for pimecrolism and tacrolism

DAZ

To protect patients, the FDA has the ability to issue special drug warnings. These appear as a black box in the information for healthcare professionals. Why has the FDA issued a black box warning for topical calcineurin inhibitors?

Delusion:

This recommendation by the FDA corresponds to particularly careful handling of the relatively new substances pimecrolimus and tacrolimus. The recommendation is based on data from animal experiments with extremely high doses and from a very small number of different malignancies in adults and children. In the past few years, around eight million people around the world have been treated with topical immunomodulators. The number of reported malignancies under treatment with these substances must be compared with an equally large group of untreated people.

To the best of my knowledge, the number of reported malignancies in the treated group is lower than in the untreated group. I think the FDA's approach to paying particular attention to children is understandable and understandable. On the other hand, it is not acceptable to draw any conclusions about the individual risk of an individual patient from this black box warning.

DAZ

What are the consequences of a US warning for Europe, especially for Germany?

Werfel:

Such a warning has no legal consequences for Europe. Nevertheless, the European authorities will also deal with these issues in terms of content.

DAZ

The Pediatric Advisory Committee believes there are indications that patients treated with topical calcineurin inhibitors have an increased risk of developing lymphoma or skin cancer in the long term. How great do you think the risk of neoplasia is when children with atopic dermatitis are treated with calcineurin inhibitors?

Delusion:

Every pediatrician will in principle exercise a very careful and critical risk-benefit assessment. For children treated with calcineurin inhibitors, there is usually only one therapeutic alternative - long-term cortisone treatment. And when weighing the benefits and risks, I am firmly convinced that calcineurin inhibitors will have to be taken into account as corticoid alternatives in the future as well.

The few cases listed by the Pediatric Advisory Committee provide no evidence of an increased risk of neoplasia in children treated with calcineurin inhibitors compared to untreated children. I would therefore be unhappy if the current discussion led to the conclusion that it is an unacceptable safety risk to use calcineurin inhibitors on a sick child and that only glucocorticoid preparations are used as a guide.

DAZ

If the current data does not indicate an increased risk of neoplasia, why did the FDA decide to take this step?

Werfel:

It is difficult to give a clear answer. From the outside it appears that the FDA has decided to act with particular caution here. Of course, it makes sense to continue to monitor new therapy principles very carefully even after they have been launched on the market. Since children in particular often suffer from neurodermatitis, it is particularly gratifying that calcineurin inhibitors are among the few new therapeutic principles that have been approved for children from the outset after carefully controlled clinical trials. Why there was a black box warning at this point in time cannot be fully understood by outsiders.

Neither the published data nor the reports of cancer after the approval of these drugs do not suggest that there is actually an increased risk of cancer in treatment with calcineurin inhibitors. It can be speculated whether the FDA would like to expressly point out with the black box warning that the use of topical calcineurin inhibitors outside of the approval is not desired and thus wants to restrict the "off-label use" which is widespread in the USA.

DAZ

A particular problem for parents and attending physicians is infants under two years of age who suffer from atopic dermatitis. Which aspects are important here for the benefit-risk assessment?

Delusion:

In most countries around the world, calcineurin inhibitors have not yet been approved for use in children under two years of age. However, there is a wide range of experiences for this age group, inter alia. from various studies. All of the safety data obtained from this indicate that no additional risk has to be accepted in therapy with topical immunomodulators. In addition, it becomes clear that the acceptance of this therapy option, in contrast to corticosteroids, is extremely high. At the moment there is also some evidence that long-term management with topical immunomodulators is more favorable than with corticoids.

Werfel:

Our clinic led the study in a large, controlled multicenter study in which infants aged three months and over were treated with topical immunomodulators for an extended period of time. From the results of this and other published studies, no safety risk could be inferred when using topical immunomodulators. However, it must be pointed out again that these preparations are currently only approved in Germany from the age of two. It would be very desirable if the pharmaceutical companies also promote approval for younger children here, which would increase legal certainty when prescribing in this age group.

DAZ

What about the occurrence of other adverse drug reactions caused by a possible weakening of the immune defense when using calcineurin inhibitors?

Werfel:

Based on the known study results, we do not assume that topical immunomodulators weaken the body's immune defenses in any way, rather the principle of therapy is a local anti-inflammatory treatment. This statement is directly supported by various clinical parameters and indirectly by the fact that no blood levels of the calcineurin inhibitors can be detected with topical therapy, or with large-area application in such a low concentration that there is no weakening of the immune system.

DAZ

In your opinion, should the use of topical calcineurin inhibitors be restricted and how do you rate the safety of these preparations in general?

Delusion:

After seven years of personal experience with these preparations, the current data have not led me to reassess the risk-benefit ratio of topical immunomodulators. We should consider ourselves lucky to have an alternative to topical corticosteroids, especially when treating young people. I am still convinced that long-term use will prove to be a safe therapeutic intervention over the years, even though - as with any innovation - no long-term data are available so far.

It goes without saying that the therapy must be monitored and documented with the necessary care, especially in very young patients. However, we should do this with the awareness that we can save a large number of children exposure to corticosteroids in a sensitive age phase or reduce it to the necessary minimum.

Werfel:

From a dermatological point of view, it should be added here that the long-term use of topical corticoids can result in special steroid side effects, such as B. on the face steroid-induced rosacea or perioral dermatitis. The long-term use of corticoids in intertriginous areas is also particularly problematic. The introduction of topical immunomodulators as an alternative to corticoids represents significant progress in the treatment of patients with neurodermatitis.

We do not want to be without these substances in practice, as they can now also be used to treat the sensitive areas of the skin. Based on experience so far, which relates to a period of seven years, I see no reason to restrict the use of calcineurin inhibitors when used as intended with regard to the safety profile at this point in time.

DAZ

Thank you for talking to us! Mw