Comparing Topical Calcineurin Inhibitors

Atopic dermatitis is characterized by chronic inflammation of the skin - the skin is red and itchy (pruritic). It is more common in the young, affecting up to 30% of children and adolescents, and up to 10% of adults.

Often symptoms come and go over a long period of time. There is no cure, but symptoms can be relieved by avoiding known triggers, using emollients to keep skin hydrated, and using topical drugs such as ant-inflammatory agents and steroids.

Topical calcineurin inhibitors are a relatively new type of medication. Two drugs, tacrolimus (0.03% and 0.1% strength) and pimecrolimus (1% strength), have been approved in the treatment of atopic dermatitis. However, several reports of serious adverse events such as skin cancer and lymphoma have led to a warning being placed on the drug's packaging.

The "Drug Class Review on Topical Calcineurin Inhibitors" compares the safety and effectiveness of two drugs. A summary of the findings is below.

How effective are calcineurin inhibitors in treating mild to moderate atopic dermatitis?

For the short-term treatment (less than 12 weeks) of mild to moderate disease, tacrolimis 0.03% ointment appears to be as effective as pimecrolimus 1% cream. Also, both medications appear to have a similar effect on improving pruritus.

For treating the head and neck regions, limited evidence suggests that pimecrolimus 1% cream may be slightly more, or as effective, as tacrolimus 0.03% ointment.

Data are lacking for higher strength tacrolimus 0.1% ointment in mild to moderate disease. 

How effective are calcineurin inhibitors in treating moderate to severe atopic dermatitis?

For the short-term treatment of moderate to severe disease, studies directly comparing tacrolimus 0.03% ointment with pimecrolimus 1% cream are lacking. Indirect comparisons from vehicle-controlled trials of tacrolimus 0.03% ointment and pimecrolimus 1% cream suggest little difference between the topical calcineurin inhibitors in treatment success, reducing pruritus, or the patient's assessment of how their dermatitis has been controlled. Results from indirect comparisons should be considered with caution due to wide variations in treatment effect (that is, large confidence interval) and small sample size.

There is mixed evidence when higher strength tacrolimus 0.1% ointment is compared with pimecrolimus 1% cream. Direct comparisons between the topical calcineurin inhibitors found tacrolimus 0.1% ointment to be more effective than pimecrolimus 1% cream, while indirect evidence found little statistical difference between the treatment groups in achieving treatment success.

In general, patients with mild to severe disease taking either tacrolimus ointment (0.03% or 0.1%) or pimecrolimus cream (1%) reported an improvement in their quality of life compared to vehicle, but evidence is lacking on whether one drug is superior to the other.

How effective are calcineurin inhibitors in treating dermatitis in the longer term?

For long-term treatment (up to 52 weeks), no evidence is available for tacrolimus and only vehicle-controlled trials exist for pimecrolimus.

Four out of five trials found that pimecrolimus 1% cream was more effective than vehicle in preventing flares and reducing topical steroid use in patients with mild to severe disease. One trial, however, found little difference between pimecrolimus 1% cream and vehicle for the number of days patients used topical steroids.

Two trials evaluated time to next flare and found that pimecrolimus was more effective in delaying flares than vehicle (up to 144 days with pimecrolimus compared to up 26 days with vehicle).

How do calcineurin inhibitors compare in harms?

There is insufficient evidence to determine how safe tacrolimus and pimecrolimus are in the long term.


Commonly reported adverse events include burning, stinging, and redness at the site where the medication is applied. These adverse events are more common with topical calcineurin inhibitors than with topical steroids or vehicle. These reactions did not significantly differ between tacrolimus (0.03% and 0.1%) ointment and pimecrolimus (1%) cream.

For rare but serious adverse events such as lymphoma, a single case-control study suggests that the risk of lymphoma is low for a small proportion of patients (1.5% to 3.0%) who had been using these medications for up to four years. The authors of this study report potential for misclassification of lymphoma cases and thus caution the reader on over interpreting the results.

Evidence regarding serious viral skin infections, skin atrophy, telengiectasia, or adrenal suppression is lacking for patients using topical calcineurin inhibitors.

Does age or gender influence effectiveness or harms?


In general, studies have not addressed whether one topical calcineurin inhibitor is more or less effective or safe in patient subgroups based on age or gender. Currently available evidence in other patient subgroups is limited to post-hoc analyses from vehicle-controlled trials and is presented below.


Single study analyses involving tacrolimus ointment (0.03% and 0.1%) found:

Patients with mild disease responded better to lower strength ointment (0.03%) than did patients with moderate disease

Patients with severe disease responded better to higher strength ointment (0.1%) than to lower strength (0.03%)

Patients with over 75% of their body surface affected with atopic dermatitis responded better to higher strength ointment (0.1%) than to lower strength (0.03%)

Black adults appeared to respond better to tacrolimus 0.1% ointment than to 0.03%

Studies involving 1% pimecrolimus cream found:

Minimal difference in treatment effect between white and non-white (black, Asian, Hispanic) patients


Infants aged 3 months to 1 year responded better than did infants aged more than 1 year (66% vs. 46%)