12 Dec 2005:
Topical immunomodulators for treatment of atopic dermatitis

Pimecrolimus cream (Elidel®, Novartis) and tacrolimus ointment (Protopic®, Johnson & Johnson) are the 2 topical immunomodulators which were granted local marketing approval in January 2003 and March 2004 respectively.


Mechanism of action

The exact mechanism of action of these drugs in atopic dermatitis (eczema) is not known. However, it has been shown that they inhibit T-cell activation and release of various cytokines (e.g. interleukins and interferon gamma).

Although these products are applied topically, low serum levels of the drugs (<2.0 ng/mL) have been detected in some patients and more frequently in children. This observed higher systemic exposure in children may be related to their greater body surface area to mass ratio.


Development in the US 1,2

Topical immunomodulators are increasingly being used in the US as first-line therapy in atopic dermatitis because they are perceived to be safer than steroid preparations. This perception of physicians and patients has been attributed to aggressive promotion of the drugs in the US market.

Prompted by concern over the increasing use of these products especially in very young children and findings of carcinogenicity in some of the animal studies as well as post-marketing reports of malignancies, the US Food and Drug Administration (FDA) issued a public advisory in March 2005. In its advisory, the FDA reminded healthcare professionals that these drugs had not been approved for use in children younger than 2 years of age. It also advised that they should be used for short periods of time and should not be used in patients who are immunocompromised.

As requested by the US FDA, the manufacturers will be conducting further research to determine the carcinogenic potential of these drugs in humans.


HSA’s assessment

In view of the development in the US, HSA and its Pharmacovigilance Advisory Committee (PVAC) have reviewed the following safety information available:

i) Animal studies
The carcinogenicity findings were not uniformly detected in all animal studies. Although some animal studies revealed no carcinogenic potential, others demonstrated some signals. For studies with positive findings, the data showed that the risk of cancer increased with increasing dose and duration of treatment. It was noted that in general the doses used in these animal studies were higher than the maximum recommended human dose (MRHD). For example, lymphoma formation in mice was reported with dermal application of tacrolimus and pimecrolimus dissolved in ethanol, at 26 times and 47 times MRHD, respectively.

ii) Post-marketing reports
As of December 2004, the US FDA reported that it received 10 and 20 cases of post-marketing reports of malignancy-related events (e.g. lymphoma) with pimecrolimus and tacrolimus, respectively. For many of these cases, the causality could not be established due to the presence of other confounding factors. To-date, HSA has not received any reports of malignance associated with pimecrolimus or tacrolimus.


Recommendations

HSA and its PVAC advise physicians to weigh the risks and benefits of the drugs for individual patients and to take into consideration the following:

  • Pimecrolimus and tacrolimus are approved for short-term and intermittent treatment of atopic dermatitis in patients unresponsive to, or intolerant of other treatments
  • They are not approved for use in children younger than 2 years old. The long term effect of these drugs on the developing immune system is not known
  • They should not be used continuously for a prolonged period of time as their long-term safety have yet to be determined.
  • Patients who are immunocompromised should not be prescribed pimecrolimus or tacrolimus


References

  1. FDA's Paediatric Advisory Committee Meeting. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm

  2. FDA Talk Paper on Elidel® and Protopic®.  http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01343.html

 
Elidel® (1%)  Licensed for short-term and intermittent long-term treatment of mild to moderate atopic dermatitis in non-immunocompromised patients who are 2 years and older in whom the use of alternative, conventional therapies is deemed inadvisable because of potential risks, or in the treatment of patients who are not adequately responsive to or intolerant of conventional therapies.
 
Protopic® (0.1%; 0.03%) Licensed for the treatment of moderate to severe atopic dermatitis in adults (0.1%) and children aged 2 years and above (0.03%) who are not adequately responsive to or are intolerant of conventional therapies. 
 


Last updated on 02 Jul 2010 16:56:43